Biomedical subjects

Mariana Kaplan

Publications and source records attributed to Mariana Kaplan.

3 recordsLinked to original sources

PubMed2005

Sera from patients with type 2 diabetes and neuropathy induce autophagy and colocalization with mitochondria in SY5Y cells.

The etiology of diabetic neuropathy is multifactorial and not fully elucidated, although oxidative stress and mitochondrial dysfunction are major factors. We reported previously that complement-inactivated sera from type 2 diabetic patients with neuropathy induce apoptosis in cultured neuronal cells, possibly through an autoimmune immunoglobulin-mediated pathway. Recent evidence supports an emerging role for autophagy in a variety of diseases. Here we report that exposure of human neuroblastoma SH-SY5Y cells to sera from type 2 diabetic patients with neuropathy is associated with increased levels of autophagosomes that is likely mediated by increased titers of IgM or IgG autoimmune immunoglobulins. The increased presence of macroautophagic vesicles was monitored using a specific immunohistochemical marker for autophagosomes, anti-LC3-II immunoreactivity, as well as the immunohistochemical signal for beclin-1, and was associated with increased co-localization with mitochondria in the cells exposed to diabetic neuropathic sera. We also report that dorsal root ganglia removed from streptozotocin-induced diabetic rats exhibit increased levels of autophagosomes and co-localization with mitochondria in neuronal soma, concurrent with enhanced binding of IgG and IgM autoimmune immunoglobulins. To our knowledge, this is the first evidence that the presence of autophagosomes is increased by a serum factor, likely autoantibody(ies) in a pathological condition. Stimulation of autophagy by an autoantibody-mediated pathway can provide a critical link between the immune system and the loss of function and eventual demise of neuronal tissue in type 2 diabetes.

Animals↗

PubMed2002

Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus.

OBJECTIVE: Inhibition of T cell DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo, suggesting that T cell DNA hypomethylation may contribute to autoimmunity. The hypomethylation effects are due, in part, to overexpression of lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18). Importantly, T cells from patients with active lupus have hypomethylated DNA and overexpress LFA-1 on an autoreactive subset, suggesting that the same mechanism could contribute to human lupus. The present study investigated the nature of the methylation change that affects LFA-1 expression in vitro and in human lupus. METHODS: Bisulfite sequencing was used to determine the methylation status of the ITGAL promoter and flanking regions in T cells from lupus patients and healthy subjects, and in T cells treated with DNA methylation inhibitors. "Patch" methylation of promoter sequences in reporter constructs was used to determine the functional significance of the methylation changes. RESULTS: Hypomethylation of specific sequences flanking the ITGAL promoter was seen in T cells from patients with active lupus and in T cells treated with 5-azacytidine and procainamide. Patch methylation of this region suppressed ITGAL promoter function. CONCLUSION: DNA methylation changes occur in specific sequences that regulate LFA-1 expression in lupus T cells and in the hypomethylation model, indicating that altered methylation of specific genes may play a role in the pathogenesis of lupus.

Adult↗

PubMed2002

Eculizumab (Alexion).

Eculizumab (5G1.1), a humanized monoclonal antibody that prevents the cleavage of human complement component C5 into its pro-inflammatory components, is under development by Alexion as a potential treatment for several chronic inflammatory diseases, including rheumatoid arthritis (RA) and nephritis [190673], [292328]. In January 2002, a phase IIb trial was initiated for RA [437814]. This trial was ongoing in April 2002, at which time, eculizumab was also in phase II trials for the treatment of membranous nephritis and lupus nephritis, and in earlier stage clinical trials for dermatomyositis and pemphigoid [446377]. The company is also developing a single-chain version of this antibody, pexelizumab, for use in acute cardiovascular indications [188760]. In October 2000, eculizumab was granted Orphan Drug status by the FDA for the treatment of dermatomyositis [385057]. In February 2002, the product received Orphan Drug designation for its use in patients with membranous nephritis [440583]. In September 2001, analysts at US Bancorp Piper Jaffray predicted eculizumab's launch for dermatomyositis and pemphigus in 2003, RA and nephritis in 2004, and chronic heart failure (CHF) after 2006 [426537]. In March 2002, analysts at US Bancorp Piper Jaffray predicted that the product would have peak worldwide sales in RA of US $175 million and US $400 million for nephritis. Sales for the RA indication are predicted to reach US $35 million in 2006, rising to US $110 million in 2008, and US $10 million in 2006, rising to US $50 million in 2008, in the US and the rest of the world, respectively. For the nephritis/other indication(s), sales are pegged at US $50 million in 2006, rising to US $200 million in 2008, and US $15 million in 2006, rising to US $100 million in 2008, again in the US and the rest of the world, respectively [446992].

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