title: Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus.
abstract: Patients with systemic lupus erythematosus (SLE) display reduced numbers and functions of invariant natural killer T (iNK T) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus-susceptible NZB × NZW F1 (BWF(1)) model. We found that iNK T cell in-vivo cytokine responses to an iNK T cell ligand α-galactosylceramide (α-GalCer) were lower in BWF(1) mice than in non-autoimmune BALB/c and major histocompatibility complex (MHC)-matched NZB × N/B10.PL F1 mice, although iNK T cell numbers in the periphery were unchanged in BWF(1) mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF(1) mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In-vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF(1) mice than in BALB/c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF(1) mice, suggesting that BWF(1) might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus-prone BWF(1) mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE.
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA.
authors.forename: J-Q
authors.initials: JQ
authors.lastname: Yang
authors.forename: P J
authors.initials: PJ
authors.lastname: Kim
authors.forename: R C
authors.initials: RC
authors.lastname: Halder
authors.forename: R R
authors.initials: RR
authors.lastname: Singh
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000276:immunology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D018655:Lymphocyte Count; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D062706:Prodromal Symptoms
chemical_list: D018949:Antigens, CD1; D005699:Galactosylceramides; D008222:Lymphokines; C493154:alpha-galactosylceramide