Increased Severity of Murine Lupus in Female Mice Is Due to Enhanced Expansion of Pathogenic T Cells

Lang, Thomas; Nguyen, Phuong; Papadimitriou, John C.; Via, Charles S.

doi:10.4049/jimmunol.171.11.5795

Cited by 37 publications

(52 citation statements)

References 28 publications

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“…The mechanisms by which sex hormones influence diabetes development in the NOD mice are not fully understood. Interestingly, it has recently been shown that the severity of autoimmune systemic lupus erythematosus in female mice is due to enhanced expansion of pathogenic T cells [38].…”

Section: Discussionmentioning

confidence: 99%

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

et al. 2004

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is frequently used in preclinical and clinical protocols to modulate autoimmune responses, bone marrow transplants, and recovery from immune ablative therapies. The immunological outcome of such therapies is not fully understood. We tested the hypothesis that GM-CSF would enhance the maturation of antigen-presenting cells, facilitating presentation of g -cell autoantigens to autoreactive T cells. We found that islet expression of GM-CSF greatly enhanced disease in male mice. Islet-derived APC but not splenic APC showed markedly enhanced capacity to stimulate in vitro proliferative responses of islet-antigen-specific autoreactive T cells. In vivo transfer of CD8 + and CD4 + T cells demonstrate that autoreactive T cells undergo extensive division in pancreatic lymph nodes of GM-CSF-transgenic mice compared with wild-type NOD male mice. Together, the results presented here demonstrate that expression of GM-CSF in the pancreas can enhance autoimmunity in disease-susceptible mice.

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Section: Discussionmentioning

confidence: 99%

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

et al. 2004

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“…SLE disease is maintained throughout life due to the presence of autoreactive/memory T cells (3,12,13). To determine whether the increase in PI3K activity is a consequence of disease (present only in activated/memory cells) or an intrinsic defect in naive T cells prior to autoantigen stimulation, we examined pathway activation in both cell subsets.…”

Section: Resultsmentioning

confidence: 99%

“…In kidney, at advanced disease phases, the mesangial proliferation, vascular collapse, and immune complex deposition result in renal failure (4,11). Deregulation of T cell homeostasis is thus a critical event in SLE; distinct T cell defects have been reported in this disease, including altered TCR signaling, reduced IL-2 production, and COX-2 upregulation (7,(12)(13)(14)(15)(16).…”

Section: S Ystemic Lupus Erythematosus (Sle) Is a Chronic Inflammatormentioning

confidence: 99%

Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death

Suárez‐Fueyo

Barber

Martínez-Ara

et al. 2011

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class IA PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.

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“…This chronic inflammatory process affects ∼1 in 1000 whites, with even higher frequencies in blacks, Native Americans, and Asians (90% of patients are females) (1)(2)(3). Current immunosuppressive therapy based on long-term corticosteroid treatment presents side effects (4,5); it is thus important to develop therapeutic approaches that are more specific.…”

Section: S Ystemic Lupus Erythematosus (Sle) Is a Complex Multigenic mentioning

confidence: 99%

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

Suárez‐Fueyo

Rojas

Cariaga

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4+ effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.

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Increased Severity of Murine Lupus in Female Mice Is Due to Enhanced Expansion of Pathogenic T Cells

Cited by 37 publications

References 28 publications

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

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