Mechanisms of activation induced by antiphospholipid antibodies in multiple sclerosis: Potential biomarkers of disease?

Multiple sclerosis (MS) is a chronic, multifactorial, inflammatory disease of the central nervous system where demyelination leads to neurodegeneration and disability. The pathogenesis of MS is incompletely understood, with prevalence of antiphospholipid antibodies (aPL) speculated to contribute to MS pathogenesis. In fact, MS shares common clinical features with the Antiphospholipid Syndrome (APS) such as venous thromboembolism. Consequently, the presence of aPL which are associated with blood clot formation in the APS need to be further investigated for a possible pro-coagulant role in the development of thrombosis in MS. The effects of IgG aPL from patients with MS upon astrocyte activation has never been characterized. We purified IgG from 30 subjects. A human astrocytic cell line was treated with 100 µg/ml IgG for 1 h, and cell extracts were examined by immunoblot using antibodies to p38 MAPK and NFκB to further examine intracellular signaling pathways induced by these IgGs. Only IgG from patients who are positive for aPL caused phosphorylation of p38 MAPK and NFκB in astrocytes. These effects were not seen with IgG from patients with MS but with no aPL or healthy controls. Understanding the intracellular mechanism of aPL-mediated astrocyte activation may help to establish new therapeutic approaches, such as selective inhibition of the mitogen-activated protein kinases, to control MS activity or possible thrombotic states.

Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells.

Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased ß-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TSC-null cells are reprogrammed to express mesenchymal-like markers. These signaling changes could be further exploited to induce clinically-relevant long-term remissions.

The possible role of an autoimmune mechanism in the etiopathogenesis of Parkinson's disease.

The clinical diagnosis of Parkinson's disease (PD) is established through clinical signs such as bradykinesia, rigidity, and resting tremor. Recently, immune system involvement has been implicated as a major pathogenic factor in the onset and progression of PD. We examine the presence of autoantibodies against phosphatidylserine (PS), cardiolipin (CL) and dsDNA in 45 PD patients and 38 healthy controls and provide evidence to the possible connection to oxidative stress. We report higher frequency of IgG anti-PS and anti-dsDNA in PD patients (24.4% and 15.6%), compared to controls (2.6% in both cases, p < 0.05). Moreover, the presence of these autoantibodies is not analogous with increased levels of oxidative stress in PD. A great need exists for improved understanding of the pathogenesis and identification of relevant biomarkers and future studies in clarifying the role of autoantibodies in PD are required to address its role as a potential risk factor.

The association between IgG and IgM antibodies against cardiolipin, ß2-glycoprotein I and Domain I of ß2-glycoprotein I with disease profile in patients with multiple sclerosis.

Antiphospholipid antibodies (aPL) occur in patients with multiple sclerosis (MS) with a number of studies reporting elevated levels; their exact prevalence and pathogenic role remain unclear. Epidemiological studies associate MS with an increased risk of deep venous thromboembolism and stroke; overlapping clinical features with APS. Antibodies against the first domain - Domain I (DI) - of ß2glycoprotein I (ß2GPI), show the most clinical significance and evidence for pathogenicity in the antiphospholipid syndrome (APS), but have not yet been investigated in MS. Serum from a well-defined cohort of 127 MS patients and 92 healthy controls were tested for IgM and IgG antibodies against cardiolipin (CL), ß2GPI and DI. Higher frequency of IgM and IgG anti-CL were found in MS patients (18.1% and 21.3%), compared to controls (1.1% in both cases, p<0.0001). We report that anti-DI antibodies were associated with MS patients, with 6.3% and 7.1% positive for IgM and IgG, respectively, compared to controls, 1.1% (p<0.05). IgM anti-CL antibodies were elevated in secondary progressive MS and primary progressive MS compared to relapse-remitting MS, (p<0.005). This study enrolled the largest number of patients with definite MS for studying the association with aPL. Although we confirmed IgM and IgG anti-CL antibodies occur in patients with MS, this is the first study that identified anti-DI antibodies in MS patients. This new finding may prove valuable and future studies are required to evaluate its role as a potential risk factor of thromboembolic phenomena in MS.