Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Abstract

Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing–remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbs in vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35–55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores and in vitro cytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and interferon-γ ex vivo. The best effect was obtained with OPN-C, which induced significantly faster and more complete remission than other OPN vaccines. In conclusion, these data suggest that production of anti-OPN autoAbs may favor remission in both MS and EAE. Novel strategies boosting their levels, such as vaccination or passive immunization, may be proposed as a future strategy in personalized MS therapy.

Synchronized expressions of serum osteopontin and B cell–activating factor in autoimmune thyroid disease

“…On the other hand, in the current study, we also attempted to explore the association of OPN levels with HT, as OPN enhances the Th1-mediated immune response, and dysregulated OPN expression was associated with cell-mediated AIDs. 12,13 However, no associations of OPN levels with HT or clinical parameters in HT patients were observed, which suggested that the role of OPN in the pathogenesis of HT might be limited. It is noteworthy that evidence has shown that cigarette smoke could induce OPN production.…”

“…Thus, the dosage of ATD usually reflects the thyroid activity and disease status during the medical therapy of hyperthyroidism. On the other hand, in the current study, we also attempted to explore the association of OPN levels with HT, as OPN enhances the Th1‐mediated immune response, and dysregulated OPN expression was associated with cell‐mediated AIDs . However, no associations of OPN levels with HT or clinical parameters in HT patients were observed, which suggested that the role of OPN in the pathogenesis of HT might be limited.…”

“…It was documented that OPN not only promotes Th1 cell differentiation, subsequently facilitating cell‐mediated immune responses, but also activates humoral immunity . Evidence showed that serum OPN concentrations are upregulated in systemic lupus erythematosus (SLE) and also modulate clinical features and prognoses of multiple AIDs . On the other hand, Xu et al reported that serum OPN levels were increased in GD patients and further suggested a possible pathogenic role of OPN in GD.…”

“…9,10 Evidence showed that serum OPN concentrations are upregulated in systemic lupus erythematosus (SLE) and also modulate clinical features and prognoses of multiple AIDs. [11][12][13] On the other hand, Xu et al 14 reported that serum OPN levels were increased in GD patients and further suggested a possible pathogenic role of OPN in GD. However, whether OPN participates in the occurrence of HT and modifies the clinical features of GD and HT is unclear.…”

Role of osteopontin in dendritic cell shaping of immune responses

“…In addition, OPN single nucleotide polymorphisms (SNPs) and OPN variants are explored as a diagnostic target to monitor several immune mediated conditions. Interestingly, recent data show that the production of anti-OPN autoAbs may favour remission in both MS and EAE, which leads to novel strategies, such as vaccination or passive immunization, to boost their levels [11,28,[124][125][126][127].…”