Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges

Abstract

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis, pregnancy morbidity and fetal loss caused by pathogenic autoantibodies directed against phospholipids (PL) and PL-cofactors. Isolated neurological APS may represent a significant diagnostic challenge, as epidemiological, clinical and neuroimaging features may overlap with those of multiple sclerosis (MS). In an open view, MS could be considered as an organ-specific anti-lipid (phospholipid and glycosphingolipid associated proteins) disease, in which autoreactive B cells and CD8+ T cells play a dominant role in its pathophysiology. In MS, diverse autoantibodies against the lipid-protein cofactors of the myelin sheath have been described, whose pathophysiologic role has not been fully elucidated. We carried out a review to select clinical studies addressing the prevalence of antiphospholipid (aPL) autoantibodies in the so-called MS-like syndrome. The reported prevalence ranged between 2% and 88%, particularly aCL and aβ2GPI, with predominant IgM isotype and suggesting worse MS prognosis. Secondarily, an updated summary of current knowledge on the pathophysiological mechanisms and events responsible for these conditions is presented. We draw attention to the clinical relevance of diagnosing isolated neurological APS. Prompt and accurate diagnosis and antiaggregant and anticoagulant treatment of APS could be vital to prevent or at least reduce APS-related morbidity and mortality.

NKT Cells in Neurological Diseases

“…Antiphospholipid syndrome is an autoimmune disorder characterized by the presence of antiphospholipid antibodies, such as anticardiolipin antibodies, anti-β2-glycoprotein 1 antibodies, and lupus anticoagulant (Schreiber et al, 2018). APS neurological manifestations have been reported to be associated with some neurological diseases including ischemic stroke and MS (Ricarte et al, 2018; D’Angelo et al, 2019). Of note, cardiolipin is among the reported lipids antigens recognized by CD1d and this recognition may explain the increased number of NKT cells in some autoimmune diseases (Cox et al, 2009; D’Angelo et al, 2019).…”

“…APS neurological manifestations have been reported to be associated with some neurological diseases including ischemic stroke and MS (Ricarte et al, 2018; D’Angelo et al, 2019). Of note, cardiolipin is among the reported lipids antigens recognized by CD1d and this recognition may explain the increased number of NKT cells in some autoimmune diseases (Cox et al, 2009; D’Angelo et al, 2019). Wermeling et al (2010) demonstrated that injection of apoptotic cells decreased the ability of type I NKT cells to produce cytokines, which further increased autoreactive B cells to produce autoreactive antibodies, such as anticardiolipin antibodies and antiphosphorylcholine, although this contrasts with the demonstration that NKT cells could promote B cell responses, and antibody production (Doherty et al, 2018).…”

Impact of Nitric Oxide Synthesis Modulators on the Cytokines Profile in Experimental Antiphospholipid Syndrome

“…The diagnostic APS criteria are anticardiolipin (aCL), antiβ2glycoproteinI (aβ2GPI) and lupus anticoagulant (LA) [1,5]. APS can be classified only in the presence of thrombotic (noninflam matory arterial, venous or small vessel thrombosis) obstetric complications (death of one or more morphologically normal fetus at or beyond the 10 th week of gestation; one or more premature birth of normal fetus before the 34 th week due to eclampsia, pre-eclampsia or placental insufficiency), or increased aPL level [2].…”

“…aβ2GPI antibodies are central in pathogenic APS mechanisms and, although the full pathogenesis of APS is not clear yet, the binding of these aPL antibodies to the antigens on the cell surface of platelets, monocytes, endothelial cells and trophoblasts triggers intracellular signaling with subsequent activation and alteration of diverse cell functions. Cellular activation starts after the binding of the complex aβ2GPI antibody/β2GPI [5,7]. β2GPI is the most important antigenic target [2].…”

“…Thrombosis at the fine vasculature of the target organ is thought to be more dependent from antibodies against the anticoagulant AnV. Endothelial cells and monocytes activation determine a proaggregation status due to up-regulated expression of adhesion molecules, such as E-selectin, and release of tissue factor (TF) and proinflammatory cytokines [5]. Many patients with aPL antibodies remain asymptomatic [2].…”