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Published on: September 12, 2016
Sphingosylphosphorylcholine inhibits plasma cell differentiation and ameliorates experimental autoimmune
Byunghyun Park1, Yu Sun Jeong1, Wonseok Hu1
1Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, Republic of Korea.
Introduction:
Multiple sclerosis (MS) is a potentially disabling disease that damages the brain and spinal cord, inducing paralysis of the body. While MS has been known as a T-cell mediated disease, recent attention has been drawn to the involvement of B cells in its pathogenesis. Autoantibodies from B cells are closely related with the damage lesion of central nervous system and worse prognosis. Therefore, regulating the activity of antibody secreting cell could be related with the severity of the MS symptoms.
Methods:
Total mouse B cells were stimulated with LPS to induce their differentiation into plasma cells. The differentiation of plasma cells was subsequently analyzed using flow cytometry and quantitative PCR analysis. To establish an experimental autoimmune encephalomyelitis (EAE) mouse model, mice were immunized with MOG35-55/CFA emulsion.
Results:
In this study, we found that plasma cell differentiation was accompanied by upregulation of autotaxin, which converts sphingosylphosphorylcholine (SPC) to sphingosine 1-phosphate in response to LPS. We observed that SPC strongly blocked plasma cell differentiation from B cells and antibody production in vitro. SPC downregulated LPS-stimulated IRF4 and Blimp 1, which are required for the generation of plasma cells. SPC-induced inhibitory effects on plasma cell differentiation were specifically blocked by VPC23019 (S1PR1/3 antagonist) or TY52159 (S1PR3 antagonist), but not by W146 (S1PR1 antagonist) and JTE013 (S1PR2 antagonist), suggesting a crucial role of S1PR3 but not S1PR1/2 in the process. Administration of SPC against an EAE mouse model significantly attenuated the symptoms of disease, showing decreased demyelinated areas of the spinal cord and decreased numbers of cells infiltrated into the spinal cord. SPC markedly decreased plasma cell generation in the EAE model, and SPC-induced therapeutic effects against EAE were not observed in μMT mice.
Conclusion:
Collectively, we demonstrate that SPC strongly inhibits plasma cell differentiation, which is mediated by S1PR3. SPC also elicits therapeutic outcomes against EAE, an experimental model of MS, suggesting SPC as a new material to control MS.
Insights
Sphingosylphosphorylcholine (SPC) inhibits B cell differentiation into antibody-producing plasma cells, mediated by S1PR3. This finding suggests SPC as a potential therapeutic agent for multiple sclerosis (MS) by reducing disease severity in an EAE mouse model.
Area of Science:
- Neuroimmunology
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a disabling central nervous system disease, historically viewed as T-cell mediated, but B-cell involvement is increasingly recognized.
- Autoantibodies produced by B cells correlate with central nervous system damage and poorer prognosis in MS patients.
- Targeting antibody-secreting cells presents a potential strategy for managing MS severity.
Purpose of the Study:
- To investigate the role of B cells and plasma cell differentiation in multiple sclerosis pathogenesis.
- To explore the potential of sphingosylphosphorylcholine (SPC) as a modulator of plasma cell differentiation and its therapeutic effects in an experimental autoimmune encephalomyelitis (EAE) model of MS.
Main Methods:
- Mouse B cells were stimulated with lipopolysaccharide (LPS) to induce plasma cell differentiation, analyzed via flow cytometry and quantitative PCR.
- An EAE mouse model was established by immunization with MOG35-55/CFA.
- The effects of SPC and sphingosine-1-phosphate receptor (S1PR) antagonists on plasma cell differentiation and EAE symptoms were assessed.
Main Results:
- Plasma cell differentiation was associated with autotaxin upregulation and sphingosylphosphorylcholine (SPC) conversion to sphingosine 1-phosphate (S1P).
- SPC inhibited B cell differentiation and antibody production in vitro by downregulating IRF4 and Blimp 1, a process dependent on S1PR3.
- In vivo, SPC administration attenuated EAE symptoms, reduced spinal cord demyelination and inflammation, and decreased plasma cell generation.
Conclusions:
- Sphingosylphosphorylcholine (SPC) effectively inhibits plasma cell differentiation via S1PR3.
- SPC demonstrates therapeutic potential in an EAE model of MS, indicating its promise as a novel agent for controlling MS.
- The therapeutic effects of SPC in EAE were dependent on B cells, as evidenced by the lack of effect in μMT mice.
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