ＤＮＡの分解異常による関節炎

Abstract

A large amount of chromosomal DNA is actively degraded during some physiological contexts such as programmed cell death and definitive erythropoiesis. DNase II is an acid DNase, and localized in lysosomes. It is required to degrade DNA of apoptotic cells after macrophages engulf dying cells, and also to degrade the nuclear DNA expelled from erythroid precursor cells. In the fetal liver and thymus of the DNase II-/- mice, there are many abnormal macrophages which carry numerous undigested DNA, and the macrophages constitutively produce IFN-β. DNase II-/- mice die in feto due to severe anemia caused by the overproduction of IFN-β.To analyze the physiological role of DNase II in adult stage, we established two mice lines : DNase II-/- IFN-IR(type-I interferon receptor)-/- mice and mice with an induced deletion of the DNase II gene. Here we show the two mice lines (referred to DNaseII deficient mice) develop a chronic polyarthritis resembling human rheumatoid arthritis (RA). Histology showed severe synovitis accompanied by pannus formation and bone erosion. A set of inflammatory cytokine such as IL-1, IL-6, and TNF-α genes was strongly activated in the affected joints of these mice. Macrophages in bone marrow and spleen accumulated undigested DNA. Both gene expression of TNF-α in bone marrow and concentration of TNF-α in serum were elevated in DNaseII deficient mice before the disease onset. The disease development was blocked by administration of neutralizing antibody against TNF-α or the loss of TNF-α gene indicating that TNF-α played an essential role for the arthritis caused by impaired DNA degradation. In contrast, Rag2 deficiency (thus lack of B cells and T cells) did not affect the onset of the disease. These results show the arthritis in DNaseII deficient mice is dependent of cytokines and innate immunity but independent of acquired immunity.These findings add an evidence to the unique concept we have proposed: "If DNA is not properly degraded, DNA causes adverse effects to organisms." We suggest an unexpected possibility that impaired DNA degradation can cause arthritis. Abnormal activation of macrophages or innate immunity may trigger the arthritis in some cases of human RA. DNase II deficient mice which show well resembling characteristics with human RA will contribute to reveal the pathology and develop beneficial therapies in RA.