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.
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| 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
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| 2. Healthy Human Kidney |
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| 3. Kidney of a Lupus Patient |
Sources
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
Image Sources
3.
http://www.niaid.nih.gov/topics/autoimmune/research/Pages/lupusKidneyDisease.aspx
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