Researchers from Stanford University School of Medicine, Yale University School of Medicine, and the Hospital for Special Surgery Research Institute has unveiled fresh insights into the immune system’s ability to prevent the production of harmful antibodies targeting the body’s healthy tissues.
Published on September 29 in the Journal of Experimental Medicine (JEM), the study sheds light on how this protective process falters in autoimmune disorders like systemic sclerosis and systemic lupus erythematosus, while also proposing promising new approaches for treating these conditions.
B cells, a subtype of white blood cells, typically defend against infections by creating antibodies that can identify and combat foreign molecules known as antigens, produced by invading pathogens like viruses and bacteria. However, some B cells generate antibodies that mistakenly target “self-antigens” produced by the body’s own cells, potentially leading to autoimmune diseases.
To prevent this, the immune system strives to eliminate self-reactive B cells during their development in the bone marrow by exposing them to self-antigens. This crucial process, known as central tolerance, was previously believed to be regulated solely by B cell receptors (BCRs) on the B cells’ surface. B cells with BCRs binding to self-antigens were assumed to be removed before leaving the bone marrow and entering the bloodstream.
However, in this new JEM study led by Eric Meffre at Yale University School of Medicine and Franck J. Barrat at the Hospital for Special Surgery in New York, researchers reveal that central tolerance also relies on a receptor called TLR9, situated within B cells in compartments called late endosomes. TLR9 is activated when it binds to fragments of DNA.
The study findings demonstrate that depleting TLR9 disrupts central tolerance, causing mice to produce more self-reactive B cells and antibodies. Interestingly, TLR9 activity is diminished in the B cells of patients with systemic sclerosis, an autoimmune disorder affecting the skin, joints, and internal organs. A similar decrease in TLR9 activity had been previously observed in the B cells of lupus patients.
The researchers pinpointed the cause of this reduced TLR9 activity as a protein called CXCL4, which, like TLR9, can bind to DNA fragments. CXCL4 levels were found to be elevated in patients with systemic sclerosis and lupus. When CXCL4 binds to DNA fragments, it prevents them from reaching late endosomes, where they would typically activate TLR9, thus inducing B cell tolerance.
Eric Meffre, who is currently a professor at Stanford University School of Medicine, noted, “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. 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.”
Source: Rockefeller University Press