Translational research : the journal of laboratory and clinical medicine
-
Whether hepatitis C virus (HCV) infection is associated with breast cancer risk remains elusive, and we aimed to elucidate it. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database (TNHIRD) was conducted. Additionally, breast cancer risk factors, and HCV core expression were surveyed in breast cancer patients of a tertiary care center. ⋯ No HCV core-positive cells were demonstrated in breast cancer tissues. Conclusions: Untreated HCV infection, urbanization, and cardiovascular events were potential risk factors for breast cancer. The HCV-associated risk was most prominent among patients <49 years, might not be associated with in situ HCV core-related oncogenesis but with metabolic alterations, and was reversed by anti-HCV therapy.
-
Pro-inflammatory immune system development, metabolomic defects, and deregulation of autophagy play interconnected roles in driving the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis (LN) is a leading cause of morbidity and mortality in SLE. While the causes of SLE have not been clearly delineated, skewing of T and B cell differentiation, activation of antigen-presenting cells, production of antinuclear autoantibodies and pro-inflammatory cytokines are known to contribute to disease development. ⋯ Moreover, genetically-driven mTOR activation has been associated with fulminant lupus nephritis. mTOR activation and diminished autophagy promote the expansion of pro-inflammatory Th17, Tfh and CD3+CD4-CD8- double-negative (DN) T cells at the expense of CD8+ effector memory T cells and CD4+ regulatory T cells (Tregs). mTOR activation and aberrant autophagy also involve renal podocytes, mesangial cells, endothelial cells, and tubular epithelial cells that may compromise end-organ resistance in LN. Activation of mTOR complexes 1 (mTORC1) and 2 (mTORC2) has been identified as biomarkers of disease activation and predictors of disease flares and prognosis in SLE patients with and without LN. This review highlights recent advances in molecular pathogenesis of LN with a focus on immuno-metabolic checkpoints of autophagy and their roles in pathogenesis, prognosis and selection of targets for treatment in SLE.
-
Lupus nephritis (LN) develops in more than a third of all systemic lupus erythematosus (SLE) patients and is the strongest predictor of morbidity and mortality. Increased circulating levels of type I interferon (IFN I) and anti-double stranded DNA (anti-dsDNA) and anti-RNA binding protein (anti-RNP) antibodies lead to increased glomerular injury via leukocyte activation and glomerular infiltration. Uncontrolled Toll-like receptor (TLR) signaling in leukocytes results in increased production of IFN I and anti-dsDNA antibodies. ⋯ Here we review the literature on the role of CD11b on leukocytes in LN. We also incorporate conclusions from several recent studies that show that these ITGAM SNPs result in a CD11b protein that is less able to suppress TLR-dependent pro-inflammatory pathways in leukocytes, that activation of CD11b via novel small molecule agonists suppresses TLR-dependent pathways, including reductions in circulating levels of IFN I and anti-dsDNA antibodies, and that CD11b activation reduces LN in model systems. Recent data strongly suggest that integrin CD11b is an exciting new therapeutic target in SLE and LN and that allosteric activation of CD11b is a novel therapeutic paradigm for effectively treating such autoimmune diseases.
-
The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus. ⋯ While there is evidence on the role of the lectin pathway in systemic lupus erythematosus, it is yet to be demonstrated whether this pathway is protective or harmful in lupus nephritis. Complement is being explored for the development of disease biomarkers and therapeutic targeting. In the current review we discuss the involvement of complement in lupus nephritis.
-
The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. ⋯ Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.