Abnormal Activation of BTK/NF-kB Identified in Acute, Remitted Cases of NMOSD

Findings from a study published in the European Journal of Medical Research showed that related cytokines in the Bruton tyrosine kinase (BTK) and nuclear factor kappa B (NF-κB) pathway were significantly higher in those in the acute and remission phases of neuromyelitis optica spectrum disorder (NMOSD) than controls, suggesting a potential role as a therapeutic target for the disease.¹

Led by Huimin Qiao, MD, Department of Neurology, Second Hospital of Hebei Medical University, the study explored the changes and possible mechanisms of the NF-κB signaling pathway and related cytokines in the pathogenesis of NMOSDs. The study, conducted from January 2018 to January 2019, included 32 patients with optic NMOSDs who were categorized into acute (n = 24) or remission (n = 8) phases, and 32 healthy volunteers as the control group.

BTK, an essential kinase in the B-cell receptor (BCR) signaling pathway, mediates multiple downstream signaling pathways, such as phosphatidylinositol 3-kinase (Pl3K), as well as inhibits nuclear factor kappa B Kinase (IKK), and NF-κB, thereby participating in cell proliferation and differentiation. In addition to evaluating the expression of BTK, Pl3K, IKK, and NF-κB, investigators also assessed cytokines chemokine ligand protein 12 (CXCL12), which exhibits chemotactic activity for monocytes, neutrophils, and early B-cell precursors, and CXC-motif chemokine receptor 4 (CXCR4), the last of which is bound to CXCL12 and is located on the membranes of B lymphocytes.

Patients in the acute phase met the criteria if they had a presence of new neurological symptoms, increased scores of 1 on the Expanded Disability Status Scale, had no immunosuppression or immunomodulation treatment before the blood sample was collected, and had no other infectious or autoimmune diseases. For the remission group, patients had no new neurological signs or symptoms, were previously diagnosed with NMOSD, and had an absence of other infectious or autoimmune diseases.

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When comparing mRNA levels, BTK, Pl3K, IKK, NF-κB, CXCL2, and CXCL12 concentration were significantly higher in the acute group than controls (all P = .000). Additionally, BTK (P = .004), IKK (P = .012), NF-κB (P = .009), CXCL2 (P = .013), and CXCL12 (P = .020) mRNA levels of those in the acute group were significantly increased compared with those in the remission group, except for Pl3K, which was significantly higher in the remission group. In comparison to controls, those in the acute and remission groups had significantly higher serum levels of CXCL2 and CXCL12 (both P <.001).

"PI3K is a key factor in the signaling pathway and is highly expressed even in the abnormal activation state of immunity during the remission period in patients with NMOSD," Qiao et al wrote. "However, the predictive value of PI3K mRNA level for disease recurrence and remission in NMOSD should be further studied in a large sample size to provide a theoretical basis for the pathogenesis and treatment strategy of NMOSD."

REFERENCE
1. Qiao H, Mao Z, Wang W, et al. Changes in the BTK/NF-κB signaling pathway and related cytokines in different stages of neuromyelitis optica spectrum disorders. Eur J Med Res. 2022;27:96