Autoimmunity is one of the most difficult to treat and unfathomable types of disease, because we are not fighting a virus, bacterium, or parasite: we are fighting our own body. Usually, doctors can count on the immune system to help them out when their patients are sick; it is the job of this system to ensure that any foreign threat to the body is eliminated. But the nature of autoimmunity is such that the biggest ally we have in the quest to keep ourselves healthy turns against us and begins attacking that which it has evolved to protect.
There are many classes of autoimmune disease, each with a very different cause. The immune system is so diverse and complicated that a mutation in one of its parts can affect the entire system and ultimately manifest in disease. There are myriad ways in which this can happen, but the result is what is called “breaking tolerance”. When tolerance is broken, the immune system recognizes some small component of the body as a foreign object and mounts an immune response against it. This can cause differing amounts of damage, depending on how prevalent the component is, and if its recognition and destruction leads to the labeling of more self proteins as targets. There is the danger of a phenomenon called epitope spreading, which happens when a cell is targeted and destroyed, releasing its contents into the body. The immune system has not been desensitized, or “tolerized” to the proteins inside a cell, as it should have no need to recognize them in a healthy body. When this happens in the context of an already active self-targeted immune response, immune cells may further target the otherwise normal contents of the dying cells, leading to a more serious attack throughout the body.
One important safeguard against autoimmunity is the safe breakdown clearance of apoptotic cells. An apoptotic cell is one that is infected, compromised, or simply too old and losing effective function. These cells are marked for uptake by phagocytes, which are a class of cell types that uptake and destroy their targets, breaking down anything in the cell that could be toxic if released into the body. It is known how and when phagocytes such as macrophages and dendritic cells destroy their targets, but the specifics of their identification are little investigated. In their paper “The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity”, Zaida G. Ramirez-Ortiz et al identify and characterize the receptor SCARF1 which, allows phagocytes to recognize their targets for destruction. SCARF1 is a transmembrane protein which has homologs even in the simple research model C. elegans, and acts by binding to a C1q and phosphatidylserine complex. Phosphatidylserine is a part of the inside of the cell membrane, and becomes exposed on the exterior portion of the membrane only when the cell needs to be phagocytosed. SCARF1, the researchers found, cannot recognize and destroy cells without this component bound to C1q, a peptide which also plays a role in the complement system. High concentrations of this peptide near a cell marked with phosphatidylserine cause a complex to form, which binds to SCARF1 and results in successful phagocytosis.
|1. Macrophage Engulfing Apoptotic Cells|
The absence of SCARF1 in mouse models was shown to cause the spontaneous contraction of an autoimmune condition that is similar to lupus (SLE), where the body recognizes cellular RNA and DNA from apoptotic cells that were not successfully phagocytosed, resulting in the breakdown of the dying cells and the release of their contents into the extracellular milieu. The SCARF1-deficient mice also exhibited spontaneous inflammation and ultimately nephritis, which is the inflammation of the kidneys, with increase in the size of glomeruli, and protein deposition. These in vivo findings support the researchers’ hypothesis of the importance of SCARF1 in the clearance of apoptotic cells and the prevention of immune disease, and provide an interesting potential primary cause for the immune disorder SLE. Future research should determine the intracellular signaling pathway associated with this process and its potential for regulation
|2. Healthy Human Kidney|
|3. Kidney of a Lupus Patient|
1. Mak, Tak W. & Saunders, Mary E: Primer to the Immune Response: Academic Cell Update edition. Academic Cell (2010).
2. Ramirez-Ortiz Zaida et al, “The scavenger receptor SCARF1 Mediates the clearance of apoptotic cells and prevents autoimmunity”. Nature Immunology. doi:10.1038/ni.2670