Anti-S-Nitrosocysteine Antibodies Are a Predictive Marker for Demyelination in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al., 1995). We report here the presence of a seemingly identical Ab response directed against SNO-cysteine in an acute model of MS, experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the 68-84 peptide of guinea pig myelin basic protein (MBP(68-84)). Serum levels of anti-SNO-cysteine Abs peaked 1 week before the onset of clinical signs and well before the appearance of anti-MBP(68-84) Abs. The anti-SNO-cysteine Ab peak titer correlated with the extent of subsequent CNS demyelination, suggesting a link between Ab level and CNS lesion formation. In relapsing-remitting MS patients, we found elevated anti-SNO-cysteine Ab at times of relapse and normal values in most patients judged to be in remission. Two-thirds of patients with secondary progressive MS had elevated anti-SNO-cysteine Ab levels, including those receiving interferon beta-1b. The data show that a rise in circulating anti-SNO-cysteine Ab levels precedes onset of EAE. Anti-SNO-cysteine Abs are also elevated at times of MS attacks and in progressive disease, suggesting a possible role for these Abs, measurable in blood, as a biological marker for clinical activity.

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…For example, the levels of natural IgM toward nitrosylated cysteine are predictive of the degree of demyelination detected in animal models of multiple sclerosis [40,202], and levels of IgM toward nitrosylated cysteine and tyrosine correlate significantly with disease severity in patients suffering from African trypanosomiasis [203]. Therefore, elevated IgM levels toward oxygen-specific epitopes and nitrosylated amino acids seen in people with major depressive disorder, multiple sclerosis, and CFS are more than biomarkers of excessive O&NS stress and damage due to O&NS, and they may be indicative of pathogenic autoimmune reactions.…”

Selective Vulnerability of Synaptic Signaling and Metabolism to Nitrosative Stress

“…Furthermore, both MS and EAE cause robust S-nitrosylation of protein cysteines in the CNS (19,20). One study demonstrated that levels of the anti-S-nitrosocysteine antibodies in plasma are elevated in EAE animals and MS patients in a manner that is predictive for the progression of the disease (28). The functional consequences of nitrosative stress in MS are still poorly understood.…”

Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

“…In addition to direct nitrosylation of protein cysteines, ONOO Ϫ can also nitrosylate highly abundant intracellular low molecular weight thiols to yield S-nitrisothiols; the latter can then trans-nitrosylate protein cysteines, including those of APLT, in cells (27). Accumulation of low molecular weight S-nitrosothiols has been detected in cerebrospinal fluid, plasma, and synovial fluid of patients with a variety of inflammation-associated diseases (57)(58)(59)(60). However, as our data with GSNO demonstrate, these extracellular S-nitrosothiols are not likely candidates as effective regulators of PS externalization and phagocytosis.…”