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Defective CD3 mediated proliferation and LPS responsiveness in multiple sclerosis
1Department of Neurology, University of Texas Southwestern Medical Center at Dallas 75235.
Abstract:
Multiple sclerosis [MS] is a chronic inflammatory disease of the central nervous system which has been postulated to be a T cell mediated disease. We examined proliferation of mononuclear cells to OKT3 mAb, Con A, ionomycin plus PMA and human myelin basic protein in subjects with relapsing-remitting and chronic progressive multiple sclerosis. Age and sex matched controls demonstrated a good proliferation to anti-CD3 mAb whereas subjects with relapsing-remitting multiple sclerosis showed a significantly decreased anti-CD3 mAb response. There was no difference in mitogen, ionomycin plus PMA or human MBP proliferation between controls and MS subjects. There was also a trend for decreasing anti-CD3 mAb proliferation in patients with chronic progressive multiple sclerosis compared to controls. LPS significantly decreased anti-CD3 mAb proliferation in controls but not in the MS subjects. An abnormality of signal transduction via the CD3 T-cell receptor complex in T cells and responsiveness to the immunomodulatory effect of IFN inducers may exist in multiple sclerosis.
Insights
Multiple sclerosis (MS) patients exhibit reduced T-cell proliferation in response to anti-CD3 monoclonal antibody (mAb), suggesting potential immune signaling defects. This impaired response was observed in relapsing-remitting MS and showed a trend in chronic progressive MS.
Area of Science:
- Neuroimmunology
- Cellular Immunology
- Autoimmune Diseases
Background:
- Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease.
- MS is widely believed to be a T-cell mediated autoimmune condition.
- Understanding T-cell dysfunction in MS is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate T-cell proliferation responses in patients with relapsing-remitting (RRMS) and chronic progressive (CPMS) multiple sclerosis.
- To compare T-cell reactivity to various stimuli, including anti-CD3 monoclonal antibody (mAb), mitogens, and myelin basic protein (MBP), between MS patients and healthy controls.
- To explore potential abnormalities in T-cell receptor (TCR) signal transduction pathways in MS.
Main Methods:
- Mononuclear cell proliferation assays were performed on subjects with RRMS, CPMS, and age/sex-matched healthy controls.
- Stimuli included OKT3 mAb (anti-CD3), concanavalin A (Con A, a mitogen), ionomycin plus PMA, and human myelin basic protein (MBP).
- Lipopolysaccharide (LPS) was used to assess its effect on anti-CD3 mAb proliferation.
Main Results:
- Healthy controls showed robust proliferation to anti-CD3 mAb.
- Subjects with RRMS exhibited significantly decreased anti-CD3 mAb proliferation compared to controls.
- No significant differences in proliferation were observed for mitogens, ionomycin/PMA, or human MBP between MS patients and controls. A trend towards decreased anti-CD3 mAb proliferation was noted in CPMS patients.
- LPS inhibited anti-CD3 mAb proliferation in controls but not in MS subjects.
Conclusions:
- T-cell dysfunction, specifically impaired signal transduction via the CD3/TCR complex, may be implicated in the pathogenesis of multiple sclerosis.
- MS patients might have altered responsiveness to the immunomodulatory effects of interferon (IFN) inducers.
- These findings highlight potential targets for immunomodulatory therapies in MS.