Enhanced Lymphoproliferation and Diminished Autoimmunity in CD4-deficient MRL/lprMice

We investigated the role of effector CD8 T cells in the pathogenesis of immune glomerular injury. BALB/c mice are not prone to autoimmune disease, but after 12 immunizations with OVA they developed a variety of autoantibodies and glomerulonephritis accompanied by immune complex (IC) deposition. In these mice, IFN-γ–producing effector CD8 T cells were significantly increased concomitantly with glomerulonephritis. In contrast, after 12 immunizations with keyhole limpet hemocyanin, although autoantibodies appeared, IFN-γ–producing effector CD8 T cells did not develop, and glomerular injury was not induced. In β2-microglobulin–deficient mice lacking CD8 T cells, glomerular injury was not induced after 12 immunizations with OVA, despite massive deposition of IC in the glomeruli. In mice containing a targeted disruption of the exon encoding the membrane-spanning region of the Ig μ-chain (μMT mice), 12 immunizations with OVA induced IFN-γ–producing effector CD8 T cells but not IC deposition or glomerular injury. When CD8 T cells from mice immunized 12 times with OVA were transferred into naive recipients, glomerular injury could be induced, but only when a single injection of OVA was also given simultaneously. Importantly, injection of OVA could be replaced by one injection of the sera from mice that had been fully immunized with OVA. This indicates that deposition of IC is required for effector CD8 T cells to cause immune tissue injury. Thus, in a mouse model of systemic lupus erythematosus, glomerular injury is caused by effector CD8 T cells that recognize Ag presented as IC on the target renal tissue.

Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 95%

IFN-γ–Producing Effector CD8 T Lymphocytes Cause Immune Glomerular Injury by Recognizing Antigen Presented as Immune Complex on Target Tissue

Tsumiyama

Hashiramoto

Takimoto

et al. 2013

“…In several experimental models of SLE, mAb treatment to eliminate T cells reduced autoimmunity (14 -16). CD4-deficient MRL/lpr mice produced few anti-dsDNA Abs, despite enhanced lymphoproliferation (17). MHC class II (MHC II)-deficient MRL/lpr mice manifested a reduction of autoantibodies (18).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

Tsao

Jiao

et al. 2008

Systemic lupus erythematosus is characterized by loss of tolerance to DNA and other nuclear Ags. To understand the role of T cells in the breaking of tolerance, an anti-DNA site-specific transgenic model of spontaneous lupus, B6.56R, was studied. T cells were eliminated by crossing B6.56R with CD4−/− or TCRβ−/−δ−/− mice, and the effects on anti-dsDNA serum levels, numbers of anti-dsDNA Ab-secreting cells, and isotypes of anti-dsDNA were analyzed. In addition, the development and activation of B cells in these mice were examined. Surprisingly, the presence of T cells made little difference in the development and character of the serum anti-dsDNA Ab in B6.56R mice. At 1 mo of age, anti-dsDNA Abs were somewhat lower in mice deficient in αβ and γδ T cells. Levels of Abs later were not affected by T cells, nor was autoantibody class switching. B cell activation was somewhat diminished in T cell-deficient mice. Thus, in the B6 background, the presence of an anti-dsDNA transgene led the production of autoantibodies with a specificity and isotype characteristic of murine systemic lupus erythematosus with little influence from T cells. TLR9 also did not appear to play a role. Although we do not yet understand the mechanism of this failure of immunoregulation, these results suggest that similar processes may influence autoimmunity associated with clinical disease.

“…ϩ T cells appear to be of paramount importance as CD4 deficiency (13) and anti-MHC class II-TCR Ab (14,15) blocked autoantibody production and ameliorated disease progression in mice. However, despite the proven importance of T cell function in the pathogenesis of SLE, the relative role of Th1 and Th2 cells remains controversial.…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

A Proinflammatory Role of IL-18 in the Development of Spontaneous Autoimmune Disease

Esfandiari¹,

McInnes

Lindop

et al. 2001

116

Serum from patients with systemic lupus erythematosus (SLE) contained significantly higher concentrations of IL-18 than normal individuals. MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease, also had higher serum levels of IL-18 than wild-type MRL/++ mice. Daily injections of IL-18 or IL-18 plus IL-12 resulted in accelerated proteinuria, glomerulonephritis, vasculitis, and raised levels of proinflammatory cytokines in MRL/lpr mice. IL-18-treated MRL/lpr mice also developed a “butterfly” facial rash resembling clinical SLE. In contrast, MRL/lpr mice treated with IL-18 plus IL-12 did not develop a facial rash. The facial lesion in the IL-18-treated mice showed epidermal thickening with intense chronic inflammation accompanied by increased apoptosis, Ig deposition, and early systemic Th2 response compared with control or IL-12 plus IL-18-treated mice. These data therefore show that IL-18 is an important mediator of lupus-like disease and may thus be a novel target for therapeutic intervention of spontaneous autoimmune diseases.