Editors' ChoiceImmunology

Genetic Clues into Lupus

STKE  20 Jun 2006:
Vol. 2006, Issue 340, pp. tw208
DOI: 10.1126/stke.3402006tw208

Systemic lupus erythematosus (SLE) is an autoimmune disease in which B cells produce antibodies directed against self components of the cell, in particular, nucleic acids and their associated proteins. Two studies offer clues to genes that may influence B cell responses and susceptibility to SLE (see the Perspective by Goodnow). Pisitkun et al. studied a genetically well-defined mouse model for SLE, in which a male-specific increase in the severity of disease is associated with the duplication of a particular X-chromosomal segment on the Y chromosome, termed the Y-linked autoimmune accelerator (Yaa). In bone-marrow mixing experiments, the autoantibodies generated by Yaa-positive cells were specific for RNA-related nucleolar antigens. These antigens also act as ligands for Toll-like receptors (TLRs), including TLR7, and further genetic characterization revealed that the duplication of the TLR7 gene by the Yaa region made the B cells in these mice more sensitive to TLR7 activation. Kumar et al., who also used a mouse SLE model, observed that a particular allelic form of the signaling protein encoded by Ly108 made B cells proliferate rather than die in response to signals that would normally maintain B cell tolerance, and allowed the B cells to make self-reactive antibodies.

C. C. Goodnow, Discriminating microbe from self suffers a double Toll. Science 312, 1606-1608 (2006). [Summary] [Full Text]

P. Pisitkun, J. A. Deane, M. J. Difilippantonio, T. Tarasenko, A. B. Satterthwaite, S. Bolland, Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669-1672 (2006). [Abstract] [Full Text]

K. R. Kumar, L. Li, M. Yan, M. Bhaskarabhatla, A. B. Mobley, C. Nguyen, J. M. Mooney, J. D. Schatzle, E. K. Wakeland, C. Mohan, Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312, 1665-1669 (2006). [Abstract] [Full Text]