Blood Serum From Relapsing MS Patients May Damage the Blood-Brain Barrier
Serum from relapsing MS patients reduced cultured brain cells’ expression of tight junction molecules and increased the expression of cell adhesion molecules that promote cytokine-activated leukocyte migration. If these serum factors are also present in plasma or whole blood, the research raises questions about the safety of blood donations from people with MS.
When cultured cells of the blood-brain barrier (BBB) are treated with serum from MS patients, the cells decrease their production of tight junction molecules and increase their production of cell adhesion molecules that promote cell migration, reported an article in the March 2014 PLOS ONE (Shimizu et al., 2014).
Breakdown of the BBB is an early feature of MS. MRI and autopsy studies reveal a damaged, leaky BBB, with disrupted tight junctions, in both active and inactive MS lesions. Once the BBB breaks down, leukocytes (activated by cytokines) can migrate across the BBB endothelium into the brain. The breakdown of the BBB and the migration of activated leukocytes across the BBB are among the earliest cerebrovascular abnormalities seen in MS brains and occur in concert with the release of inflammatory cytokines.
Fumitaka Shimizu of Yamaguchi University Graduate School of Medicine in Ube, Japan, and colleagues evaluated the effect of blood serum from MS patients on cultures of human brain microvascular endothelial cells (BMECs) of the TY09 cell lineage. They collected serum from 29 subjects, including six healthy controls, six currently relapsing RRMS patients, nine stable RRMS patients, and eight SPMS patients.
A complex pattern of results emerged. For example, sera from both SPMS and relapsing RRMS patients reduced the expression of the tight junction protein claudin-5 in cultured BMECs.
Both serum and purified immunoglobulin G from all types of MS patients increased the expression of the vascular cell adhesion protein VCAM-1. VCAM-1 is a cell surface protein expressed by cytokine-activated endothelium that mediates the adhesion of leukocytes to the vascular endothelium.
Shimizu et al. wrote, “Our present study demonstrated that the sera from patients with relapsing MS or SPMS can induce the BBB breakdown.” In contrast, serum from MS patients in the stable, remission phase of RRMS did not suppress the expression of claudin-5, the tight junction protein.
The researchers also looked at MMP-2/9, a proteinase that can open the BBB by damaging tight junction proteins such as claudin-5 and occludin. Expression of MMP-2/9 increased in BMECs after the cultured cells were exposed to sera from relapsing RRMS patients—but not after exposure to sera from SPMS or stable RRMS patients.
Finally, when serum from relapsing RRMS patients was pretreated with the drug GM6001—an MMP inhibitor—the cultured cells expressed normal amounts of claudin-5. In short, GM6001 inhibited MMP so it could not depress claudin-5 levels, “rescuing” the BBB. It’s conceivable that GM6001 might have therapeutic value for inhibiting BBB damage in relapsing patients. As Shimizu et al. wrote, “A previous report suggested that treatment of GM6001 ameliorates EAE [experimental autoimmune encephalomyelitis] by repairing the disruption of the BBB.”
If Shimizu’s work also applies to whole blood or plasma in living patients, it could potentially raise questions about the safety of blood donations by MS patients. According to a spokeswoman at the American Red Cross, “multiple sclerosis has not been a cause for blood donation deferral since at least 2005. If a donor has MS, but feels healthy and well and meets all other eligibility criteria, he/she should be able to donate blood.”
Key open questions
- Were these 29 subjects representative of MS patients generally?
- Do the observed differences in gene expression result in a damaged BBB in vivo?
- Might the effects of blood or plasma be different than those of serum?
- What kind of experimental design would be required to demonstrate these effects in vivo?
Disclosures and sources of funding
This work was supported in part by research grants from the Japan Society for the Promotion of Science, Tokyo, Japan, by a Health and Labor Sciences Research Grant for research on intractable diseases from the Ministry of Health, Labor and Welfare of Japan and also by a Translational Research Promotion Grant from Yamaguchi University Hospital. The authors have declared that no competing interests exist.