Toll-like receptor 7- dependent loss of B cell tolerance in pathogenic autoantibody knockin mice

Speaker: 林怡璇                          Date: 2006/11/08 13:10~14:00

Commentator: 楊倍昌 老師                Place: Room 601

Abstract:

    Toll-like receptors (TLRs), which play a crucial role in innate immune response, can detect pathogen-associated molecular patterns and activate antimicrobial response. TLRsare also capable of recognizing self-antigens released from stressed or damaged host tissues, and such self-recognition can potentially promote the development of autoimmune disease, such as systemic lupus erythematosus (SLE)^[1]. In general, TLR7 and TLR9 respectively recognize virus or bacteria single-strand RNA and double-strand DNA inendosome of the host cells, and in large part, activation of these receptors by host nucleic acid is avoided by their intracellular localization^[2]. However, recent in vitro study demonstrated that if host DNA or RNA is delivered to the appropriate compartment by receptor-mediated endocytosis, it will lead to B cells activation and proliferation. But in normal circumstances, a variety of B cell tolerance mechanisms are believed to prevent these cells from becoming activated. In order to better understand how B cells reactivedby these kinds of antigens are regulated in non-autoimmune C57BL/6 mouse strain, the investigators generated a transgenic mouse line, 564Igi, which produced a pathogenicpolyreactive antibody that reacted with ssDNA, ssRNA, and nucleosomes. They found that B cells expressing this immunoglobulin and producing class-switched autoantibody in vivo despite the apparently normal induction of anergy, were largely dependent on TLR7. They further found that production of these autoantibodies was sufficient to cause kidney pathology in these mice, and demonstrated nucleic acid-containing autoantigens that caused sever disease lie in their ability to bind both antigen receptor and TLR7^[3].

References:

1.          Lau, C. M., et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171-1177 (2005)

2.          Christensen, S. R., et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus.Immunity 25, 417-428 (2006)

3.          Berland, R., et al. Toll-like receptor 7-Dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429-440 (2006)