VLA-4: Its Role in Immunity, Disease, and Treatment

On the surface of the body’s cells are countless proteins, including a molecule known as Very Late Antigen-4, or VLA-4. This protein is a subject of scientific interest because of its central function in the immune system. Found predominantly on the surface of immune cells, it acts as a director of cellular traffic. Proper VLA-4 function is necessary for health, but its actions can also contribute to certain diseases, making it a target for medical intervention.

Understanding VLA-4: A Key Cellular Gripper

VLA-4 belongs to a family of proteins called integrins, which connect cells to each other and their surrounding environment. VLA-4 is a heterodimer, constructed from two linked protein chains: an alpha-4 (α4) subunit and a beta-1 (β1) subunit. This integrin is primarily expressed on immune cells like lymphocytes, monocytes, and eosinophils, but is absent from neutrophils.

The presence of VLA-4 on these cells is related to their need to travel out of the bloodstream and into tissues, a process mediated by its interaction with partner molecules called ligands. The two main ligands are Vascular Cell Adhesion Molecule-1 (VCAM-1) and fibronectin. VCAM-1 is found on endothelial cells lining blood vessels, while fibronectin is a protein in connective tissues.

This binding is not always active, as VLA-4 can exist in a low-affinity, or non-gripping, state. It requires activation by chemical signals called chemokines to switch into a high-affinity state where it can firmly bind its ligands. This regulation ensures that immune cells only adhere and migrate at appropriate times and locations.

How VLA-4 Directs Immune Cell Traffic

The primary role of VLA-4 is to guide the movement of immune cells from the circulation into tissues, a process called extravasation, which is necessary for immune surveillance and responding to injury. This process begins when inflammatory signals cause endothelial cells lining blood vessels to increase their expression of VCAM-1. As immune cells with VLA-4 flow past, the interaction with VCAM-1 slows them, causing them to roll along the vessel wall.

Following this initial, low-affinity tethering, chemical signals activate VLA-4 into its high-affinity state. This change causes the cell to grip VCAM-1 tightly, leading to firm adhesion that stops its movement. Once firmly attached, the immune cell squeezes between the endothelial cells into the surrounding tissue, a step known as diapedesis.

Once inside the tissue, VLA-4 continues to play a part by interacting with fibronectin in the extracellular matrix. This allows the immune cell to navigate through the tissue to the precise location of the problem, ensuring defensive cells are recruited efficiently.

VLA-4’s Involvement in Disease Processes

While the trafficking of immune cells is a necessary defense, the process becomes destructive if misdirected. In many autoimmune and inflammatory diseases, VLA-4 facilitates the inappropriate migration of leukocytes into protected tissues, leading to sustained inflammation and damage.

Multiple sclerosis (MS) is a primary example. In MS, the body’s immune cells attack the myelin sheath insulating nerve fibers in the central nervous system (CNS). VLA-4 enables these autoreactive T-cells to cross the blood-brain barrier, which normally protects the brain from circulating cells.

The interaction between VLA-4 on lymphocytes and VCAM-1 on the endothelial cells of the blood-brain barrier allows this damaging infiltration to occur. Once inside the CNS, these immune cells release inflammatory substances that damage myelin and nerve cells, leading to the neurological symptoms of MS.

A similar mechanism contributes to Crohn’s disease, an inflammatory bowel disease (IBD). In this condition, VLA-4 guides an excessive number of inflammatory cells into the lining of the gastrointestinal tract. This influx perpetuates a cycle of inflammation that damages the intestinal wall.

Targeting VLA-4 for Medical Treatments

Given its role in harmful inflammation, VLA-4 is a target for therapeutic intervention with drugs called VLA-4 inhibitors. These drugs physically block the protein from binding to its ligands. This action stops immune cells from migrating into tissues where they cause damage.

A prominent example is Natalizumab, a monoclonal antibody approved for multiple sclerosis and Crohn’s disease. Natalizumab binds to the alpha-4 subunit of VLA-4, preventing it from locking onto VCAM-1 on blood vessel walls. This reduces the migration of immune cells into the CNS or gut tissue, which lessens inflammation and slows disease progression.

However, interfering with the immune system carries substantial risks. The most serious side effect is an increased risk of Progressive Multifocal Leukoencephalopathy (PML). PML is a rare brain infection caused by the John Cunningham (JC) virus, a common virus that is typically kept dormant by the immune system.

By blocking VLA-4, Natalizumab impairs the immune surveillance that normally controls the JC virus. This can allow the virus to reactivate and destroy brain tissue. This risk requires careful patient selection and monitoring, including testing for JC virus antibodies to assess an individual’s risk before and during treatment.