The role of the Yaa gene in lupus syndrome.
The BXSB/MpJ (BXSB) murine strain (H-2b) spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females. A mutant gene located on the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), is responsible for the acceleration of the disease observed in male BXSB mice. Studies on H-2 congenic and I-E transgenic mice have clearly demonstrated that the MHC class II genes play a crucial role in the development or protection of SLE. However, the MHC effect can be completely masked by the presence of the Yaa gene in mice with certain genetic backgrounds. It is intriguing that the Yaa gene effect is selective on autoimmune responses, varying in different lupus-prone mice. Studies on immune responses against foreign antigens have shown that the Yaa gene potentiates immune responses only against antigens to which mice are genetically (H-2-linked) low-responding, but not high-responding. Thus, the selective immune enhancing activity of the Yaa gene may be related to differences in the capacity of T helper cells specific for given antigens. Moreover, studies on Yaa(+)-Yaa- bone marrow cell chimeric mice have suggested that a specific cognate interaction of T helper cells with Yaa+ B cells is responsible for a selective enhancing effect of immune responses to foreign antigens as well as autoantigens. It is significant that unlike the lpr mutation, whose abnormality is associated with the capacity of the Fas antigen to mediate apoptosis, the Yaa gene by itself is unable to induce significant autoimmune responses in mice without apparent SLE background. This suggests that the molecular defect of the Yaa gene is likely to differ from that of the lpr gene, and that the Yaa gene effect requires the abnormal autosomal genome present in lupus-prone mice. Based on these findings, a possible molecular nature of the Yaa gene abnormality will be discussed.
Izui
S
S
Department of Pathology, University of Geneva, Switzerland.
Merino
R
R
Fossati
L
L
Iwamoto
M
M
D000818:Animals; D001323:Autoantibodies / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D014998:Y Chromosome / Q000235:genetics*
D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II