A role for fungal ▀-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice

JEM, Volume 201, Number 6, 949-960
Published 21 March 2005. doi:10.1084/jem.20041758

A role for fungal ▀-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice

Hiroyuki Yoshitomi1,2, Noriko Sakaguchi1,3, Katsuya Kobayashi4, Gordon D. Brown5, Tomoyuki Tagami1, Toshiko Sakihama1, Keiji Hirota1, Satoshi Tanaka1, Takashi Nomura1, Ichiro Miki4, Siamon Gordon6, Shizuo Akira7, Takashi Nakamura2, and Shimon Sakaguchi1,3,8
1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University
2 Department of Orthopedic Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
3 Laboratory for Immunopathology, Research Center for Allergy and Immunology, Institute of Physical and Chemical Research, Yokohama 230-0045, Japan
4 Department of Allergy, Pharmaceutical Research Center, Kyowa Hakko, Ltd., Shizuoka 411-8731, Japan
5 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
6 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK
7 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
8 Core Research for Evolutional Science and Technology, Science and Technology Agency of Japan, Kawaguchi 332-0012, Japan

CORRESPONDENCE Shimon Sakaguchi: shimon@frontier.kyoto-u.ac.jp

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal ▀-glucan, or purified ▀-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major ▀-glucan receptor, can prevent SKG arthritis triggered by ▀-glucans, which strongly activate dendritic cells in vitro in a Dectin-1ľdependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.

Abbreviations used: CP, cyclophosphamide; ITS1, internal transcriber spacer 1; poly(I:C), polyinosinic-polycytidylic acid; PTX, pertussis toxin; RA, rheumatoid arthritis; SPF, specific pathogen-free; TLR, Toll-like receptor.
H. Yoshitomi and N. Sakaguchi contributed equally to this work.

T. Tagami's present address is Ajinomoto Co., Inc., Kawasaki 210-8681, Japan.

T. Sakihama's present address is Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.