Natalizumab (Tysabri) Targets Molecule Crucial for Type of B-Cell to Accumulate in the Brain

Mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), were found to have milder symptoms if the target of natalizumab (Tysabri) — VLA4 — was absent on B-cells, preventing regulatory cells that might control immune processes from entering the brain.

B-cells are increasingly thought to play a role in autoimmune processes in the brain. Earlier studies have also shown that Bregs, a type of B-cell with regulatory properties, might be involved in suppressing EAE.

VLA4 is a molecule expressed on the surfaces of B-cells and the target of natalizumab. The expression of the molecule has been shown to mediate important steps in the autoimmune process: when VLA4 is blocked, fewer B-cells accumulate in the brain during EAE, suggesting that natalizumab works in RRMS in part by blocking B-cell accumulation.

B-cell actions, however, are complex, being composed of both immune mediating and immune controlling cells.

Researchers at the University of California, San Francisco, explored if VLA4 was also an important factor in allowing Bregs to accumulate in the brain, speculating that the lack of Bregs in mice might explain their more severe EAE symptoms.

In the study, “CNS accumulation of regulatory B cells is VLA-4-dependent,“ researchers studied EAE in mice lacking VLA4 on B-cells using two different techniques. One method was dependent on the activation of B-cells while the other was not.

Their findings, presented in the journal Neuroimmunology and Neuroinflammation, showed that in mice lacking VLA4, EAE was less severe than in control mice when the researchers used the B-cell dependent method. In contrast, animals got sicker when EAE was induced by the B-cell independent method.

In mice lacking the natalizumab target having B-cell independent EAE, researchers noted that fewer B-cells had accumulated in the central nervous system. Particularly, the team found that virtually no Bregs had entered the brains of the mice with more severe EAE.

The findings underscore the complexity of autoimmune processes in MS. While researchers speculate that natalizumab might function by preventing brain B-cell–mediated immune reactions, the experiments showed that preventing regulatory B-cells from entering the brain produces more severe symptoms.

Because VLA4 is also present on immune T-cells, researchers are still ultimately in the dark regarding the contributions of the various cell types to MS. The study, however, provides evidence that Bregs counteract the autoimmune processes, at least in mice, and highlights the need to choose the right EAE model when studying B-cell processes.