Significance of MHC class II haplotypes and IgG Fc receptors in SLE.
Systemic lupus erythematosus (SLE) is a systemic antibody-mediated autoimmune disease that develops under the control of multiple susceptibility genes. Genetic studies in murine and human SLE have identified several chromosomal intervals that contain candidate susceptibility genes. However, the ultimate identification of the genes and their roles in disease process need much further investigation. Spontaneous murine SLE models provide useful tools in this respect. In this chapter, we show this line of investigation, particularly focusing on the roles of major histocompatibility complex (MHC) class II and immunoglobulin G Fc receptors (FcgammaRs). The existence of high-affinity autoantibodies is evidence that autoimmunity in SLE is antigen-driven. Thereby, MHC class II haplotypes have been implicated in SLE susceptibility; however, because of the linkage disequilibrium that exists among the class I, II and III genes within the MHC complex, it has been difficult to discriminate the relative contributions of individual loci. On the other hand, the extent of antibody synthesis upon antigen stimulation and associated inflammatory cascades are controlled in several ways by the balance of stimulatory and inhibitory signaling molecules on immune cells. Stimulatory/inhibitory FcgammaRs mediate one such mechanism, and there are reports indicating the association between polymorphic FcgammaRs and SLE. However, as stimulatory and inhibitory FcgammaRs cluster on the telomeric chromosome 1, the absolute contribution of individual genes has been difficult to dissect. In studies of genetic dissection using interval-congenic and intragenic recombinant mouse strains of SLE models, we show evidence and discuss how and to what extent MHC class II molecules and stimulatory/inhibitory FcgammaRs are involved in SLE susceptibility.
Hirose
Sachiko
S
Department of Pathology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. sacchi@med.juntendo.ac.jp
Jiang
Yi
Y
Nishimura
Hiroyuki
H
Shirai
Toshikazu
T
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D002875:Chromosomes / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology
D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II; D017452:Receptors, IgG