Scientists at Stanford University School of Medicine, Yale University School of Medicine, and the Hospital for Special Surgery Research Institute have discovered new insights into how the immune system prevents the production of antibodies that can recognize and damage the body’s own healthy tissues.
The study was published in the Journal of Experimental Medicine (JEM) in an article titled, “TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance.”
“Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells,” the researchers wrote. “Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides.”
The research teams led by Eric Meffre, PhD, who was an associate professor at Yale University School of Medicine and is now a professor at Stanford University School of Medicine, and Franck J. Barrat, PhD, the Michael R. Bloomberg chair in autoimmune diseases at the Hospital for Special Surgery in New York report that central tolerance also depends on a receptor called TLR9. This receptor is located inside B cells in compartments known as late endosomes and is activated by binding to fragments of DNA.
They discovered that depleting TLR9 impairs central tolerance and causes mice to produce increased numbers of self-reactive B cells and antibodies.
The researchers determined that this reduction in TLR9 activity is due to a protein called CXCL4, which, like TLR9, can bind to DNA fragments. CXCL4 levels are elevated in patients with systemic sclerosis and lupus, and the researchers found that, when it binds to DNA fragments, CXCL4 prevents them from being delivered to late endosomes, where they would normally be able to activate TLR9 and induce B cell tolerance.
“Our data challenge the current paradigm that BCR signaling alone is responsible for the deletion of self-reactive B cells in the bone marrow, since we demonstrate that TLR9 signaling plays an essential role in the establishment of central B cell tolerance,” said Meffre. “Correcting defective TLR9 function in B cells from patients with systemic sclerosis and perhaps other autoimmune diseases, potentially by neutralizing CXCL4, may represent a novel therapeutic strategy to restore B cell tolerance.”
