The Institute of Medical Science, The University Of Tokyo

  1. Home
  2. Scientific Papers

Scientific Papers/Award

Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells

Nature Medicine (On line 10.1038/nm1697)
Noriyuki Fujikado1, Shinobu Saijo1, Tomo Yonezawa1,2, Kazusuke Shimamori1, Akina Ishii1, Sho Sugai1, Hayato Kotaki1,4, Katsuko Sudo1,4, Masato Nose3 & Yoichiro Iwakura1
1. Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
2. Genodive Pharma, 411 Ikehata, Isehara-shi, Kanagawa 259-1144, Japan.
3. Department of Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
4. Present addresses: Genodive Pharma Inc., 411 Ikehata, Isehara-shi, Kanagawa 259-1144, Japan (H.K.); Animal Research Center, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan (K.S.).

The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine–based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen–immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony–stimulating factor, Dcir-/- mouse–derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.