Brain-derived neurotrophic factor precursor in the immune system is a novel target for treating multiple sclerosis

Abstract

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75 NTR ) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.

Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy

“…We also observed that an intraperitoneal injection of mAb-proBDNF highly alleviated the fear conditioning memory in SAE mice, which was accomplished by perturbing the peripheral proinflammatory response (Luo et al, 2020). In our latest study, we confirmed that mAb-proBDNF treatment can attenuate multiple sclerosis in a mouse model and inhibit the proinflammatory response in the spinal cord and spleen of diseased mice (Hu et al, 2021). In the current study, our results showed that both intrahippocampal microinjection (Figure 4) and the systemic delivery (Figure 5) of mAb-proBDNF improved the cognitive impairment in SAE mice, this may be due to the inhibition of the inflammatory response of the CNS and/or peripheral system.…”

Brain‑derived neurotrophic factor in autoimmune inflammatory diseases (Review)

“…EAE is histologically and clinically similar to MS, which was established in an animal model to study autoimmune demyelination ( 11 , 39 ). Myelin-reactive T cells of the CNS produce and release BDNF to promote post-traumatic tissue repair ( 39 ).…”

“…Of note, transfection of T cells expressing BDNF strongly reduced brain damage in EAE and protected axons ( 40 ). Elevated serum BDNF levels have also been associated with nerve repair in patients with MS ( 11 ).…”

“…Of note, the production of BDNF varies among different T lymphocyte subpopulations ( 5 ). BDNF has been linked to systemic lupus erythematosus (SLE) ( 9 ), experimental autoimmune encephalomyelitis (EAE) ( 10 ), multiple sclerosis (MS) ( 11 ) and other autoimmune inflammatory diseases. SLE involves dysregulation of T and B lymphocyte networks ( 12 ).…”

Up-regulation of proBDNF/p75 NTR signaling in antibody-secreting cells drives systemic lupus erythematosus

“…Up-regulation of proBDNF in CD4 + T cells regulates sepsis-associated encephalopathy ( 25 ). Recently, we reported that proBDNF-p75 NTR signaling is up-regulated in the lymphocytes of both patients with multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE) mouse models ( 26 ); a monoclonal antibody against proBDNF (McAb-proB) was found to attenuate clinical scores, limit demyelination, and inhibit proinflammatory cytokines in EAE mice ( 26 ). These results suggest that proBDNF signaling released from B cells may implicate into the pathogenesis of autoimmune diseases.…”