T- and B-cell abnormalities in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of antinuclear autoantibodies and clinical involvement in multiple organ systems. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Abnormal expression of key signaling molecules, defective signal transduction pathways, and permanent mitochondrial dysfunction--associated with a significantly increased mitochondrial mass--appear to be the axis of T-lymphocyte dysfunction. Lupus T cells exhibit persistent mitochondrial hyperpolarization (MHP), cytoplasmic alkalinization, increased ROI production, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and may account for increased interferon-alpha production, inflammation, and antinuclear antibody production. Recent data indicate that B cells are not merely the passive producers of autoantibodies, but also play a central role in autoimmunity via nonconventional mechanisms, including autoantigen presentation and modulation of other immune cells. This article reviews recent advancements in the understanding of the molecular mechanisms involved in the pathogenesis of lupus autoimmunity and highlights the development of novel therapies in SLE.
Nagy
Gyorgy
G
Section of Rheumatology, Department of Medicine, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY 13210, USA.
Koncz
Agnes
A
Perl
Andras
A
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; D004967:Estrogens