Natalizumab, B cells and Multiple Sclerosis

Research Summary: Cutting Edge: Integrin a4 is required for regulatory B cell control of experimental autoimmune encephalomyelitis

The background

For a long time, multiple sclerosis was regarded as an autoimmune disease that was caused by T cells.  However, evidence has grown in recent times that suggests that B cells may actually play an important role in the pathogenic process in MS.  Studies have shown that they can do this by stimulating the T cell response, as well as by releasing molecules that create an inflammatory environment.  However, as with T cells, it has also been revealed that B cells can have a regulatory effect on the disease process by inhibiting cells of the immune system that are causing damage, and by releasing anti-inflammatory signals.  These types of cells are referred to as regulatory B cells or Bregs.

Natalizumab (Tysabri) is a powerful MS medication that works primarily by binding to and blocking part of the VLA-4 molecule, known as integrin alpha-4.  The VLA-4 molecule has been shown to be important in helping autoreactive T cells move across the blood brain barrier and into the central nervous system.  However, the use of this therapy has also been associated with a severe and fatal disorder called progressive multifocal leukoencephalopathy (PML).

The study

This study, conducted by researchers at Benaroya Research Institute and University of Washington, aimed to improve the understanding of how natalizumab treatment may impact on the function of Bregs.  To mimic the effect that natalizumab treatment has on B cells, mice were created that lack integrin alpha-4.  These mice, as well as normal or ‘wildtype’ mice, were then treated in such a way as to develop EAE (the animal model of MS).

The findings

The study enabled a number of results to be identified, including:

• Mice with B cells lacking integrin alpha-4 developed EAE with a worse clinical severity
•  The worsening of disease was associated with an increase in pathogenic T cells and a decrease in B cells in the CNS in these mice
•  B cells from a particular region of the spleen, known as the marginal zone, were found to be the main producers of anti-inflammatory molecules.  They were also found in much higher numbers in the spleen than the CNS, indicating that their regulatory activities probably occur there.
• Transferring B cells from ‘wildtype’ mice into the integrin alpha-4 deficient mice prior to inducing EAE resulted in disease severity being reduced back to the levels seen in normal mice.

The outcomes

This study has a couple of potentially important outcomes for people with MS.  Firstly, it has identified that regulatory B cells can play an important role in helping to reduce the severity of the disease by dampening the damage-causing or pathogenic T cell response.  Understanding this interaction better could lead to the development of improved MS therapies.

Secondly, this could provide some information as to a role for Bregs in containing the JC virus and stopping the development of PML.  As this wasn’t studied directly in this paper, further work will need to be done to assess whether this is the case.  A better understanding of this could lead to improving the safety profile of natalizumab and minimizing the risks associated with it.

The abstract of this study can be found here.