Much of my past writings have been about the immune system, given my education and the pandemic. Most of these discussions of the immune system have focused on antibodies and immune cells, but have left out the many free-floating proteins that play several important roles in the immune response. The role these complement proteins play in our immune system is still an area of significant study that isn’t well understood; protein interactions are difficult. But if you have heard the terms “cytokine storm” or “complement activation” in the media during the pandemic, you’re at least somewhat aware of how big a part these proteins play. So today, let’s give these unsung heroes their due.
The Basics
Evolutionarily, the complement system is the oldest part of the immune system, existing in a similar shape as today for almost 500 million years. It consists of about 30 unique small proteins, produced primarily by the liver that passively circulate through the bloodstream. These proteins will continue circulating indefinitely, until they come across a pathogen. There are three separate mechanisms for how the complement system can be activated. Firstly, the process has a very small chance of activating itself at random, which creates a constant low-level deterrence against disease. Secondly, bacteria and viruses have certain sugars on their bodies that aren’t normally found on the exteriors of human cells, so certain complement proteins will stick to those sugars. Finally, and most notably, when antibodies bind themselves to a pathogen, there are complement proteins that attach themselves to those antibodies. (Figure 1) However it starts, the result is a pathogen with complement proteins stuck to it. Other free-floating complement proteins will come across these proteins and stick to them, like a puzzle assembling itself on the back of a germ. The finished product is a structure called C3 convertase. For most viruses, which are usually only slightly larger than single proteins, having this large protein complex on its back can make it impossible to enter other cells to infect them. For bacteria and larger pathogens, the cascade is only beginning. As its name suggests, C3 convertase’s job is to convert C3, which is another free-floating complement protein that the convertase grabs and cuts in half. The smaller half, C3a, floats through the blood where immune cells can “smell” it, allowing them to track the pathogen like they’re following a trail of breadcrumbs. The larger half, C3b, sticks to the bacteria’s back where other complement proteins bind to it to create more C3 convertase. This leads to an accelerating cascade where more and more C3 convertase complexes are created on the bacteria’s back. The proteins crowding around the bacteria make it harder to move. The trail of C3a particles attracts the attention of nearby immune cells. Many bacteria evolve to have slippery surfaces that make it harder for immune cells to grab hold of them, but C3 convertases act as handholds for these immune cells to grab hold of bacteria and eat them. And if all that fails, more complement proteins are recruited to attach to the bacteria and create a membrane attack complex. (Figure 2) This structure punches a hole in the bacteria that can’t be closed, and since all cells rely on maintaining a careful balance of salt ions inside themselves to function, this hole can disable or kill the bacteria completely. For more details, I highly recommend this video from Kurzgesagt.
Fig. 1. Complement protein C1 (blue) Fig. 2. Membrane Attack Complex
binding to antibodies (orange)
When immune cells detect C3a particles floating in the blood, it's read as a sign of an ongoing attack. One of the many steps they take in preparing for battle is the secretion of cytokines. Cytokine is the name given to over 200 proteins (including C3a) involved in cell signaling related to immune function. This is how immune cells communicate with each other and with non-immune cells. Certain classes of cytokines are secreted by immune cells to give instructions to other immune cells (come here, switch on, reproduce faster, don’t die yet, etc.) as well as to nearby blood vessels and tissues. The most important role of cytokines is to trigger inflammation, where blood vessels open up slightly and let fluid leak out into the surrounding tissue.* Fluid builds up in the tissue, making it easier for immune cells to swim around. As blood flow is directed to the inflamed tissue, immune cells and complement proteins build up to clear out pathogens and damaged cells. These same cytokines also make blood vessels more permeable to immune cells, making it easier for defenders to enter the tissue. Immune cells produce cytokines that modulate cell growth to aid with wound healing and complement proteins tag damaged cells and cell detritus for destruction and removal by immune cells. Other types of cytokines are produced exclusively by civilian cells (non-immune cells). When civilian cells are damaged, they secrete cytokines that get the attention of repair and disposal cells. When a cell is infected by a virus, it will attempt to secrete cytokines that attract immune cells as well as warn neighboring cells of the danger. These neighboring cells will change what proteins they express, becoming harder to infect and easier for immune cells to inspect. The exact function and mechanism behind each of the over 200 unique cytokines is still being researched, protein signaling and interactions are extremely complicated. But the closer scientists look at the complement system and cytokine interactions, the more they appear to be the bedrock of the entire immune system.
Covid-19 and Cytokines
I’ve talked before about the strict regulation the immune system requires to prevent it doing damage to the body, and the complement system is no different. C3 proteins have a low chance of randomly activating and targeting the nearest cell, be it pathogen or body cell. If a body cell winds up getting tagged by complement proteins, it will wind up being targeted by the immune system or destroyed by membrane attack complexes. So to keep the complement system in check there is a class of complement control proteins. This includes proteins floating in the blood and proteins on the membranes of civilian cells that disable and detach complement proteins that mistakenly tag healthy body cells. When these control proteins don’t work properly, complement misfiring can be linked to diseases ranging from age-related macular degeneration to certain forms of schizophrenia. But that is from slow, chronic over-action of the immune system, created by genetic disorders. Sudden powerful bursts of immune activity can be even more destructive.
During the height of the Covid-19 pandemic, the most common way to die from Covid was via a cytokine storm. This is when the immune system responds to a severe illness by over-producing inflammatory cytokines, causing damage to surrounding tissue. Inflammation is good when it is temporary and controlled, but long-term or severe inflammation is dangerous. Inflammation of the lungs can constrict airways and prevent breathing. The swelling of tissue can put mechanical stress on tissue which can over time cause damage. Cells experiencing these stresses will age faster and lose function over time. When tissue is too severely damaged, it has to be repaired with scar tissue that causes long-term disability. Cytokines also trigger blood coagulation so as to facilitate scabbing to prevent blood loss. Cytokine storms can cause so much coagulation that blood clots form, which are particularly dangerous in narrow capillaries such as those of the lungs. Even though this storm is centered on the lungs, cytokines can enter the bloodstream and trigger similar severe inflammation in other organs. And because immune cells respond to cytokines by reproducing faster and these new immune cells produce more cytokines, one could get trapped in a feedback loop of ever escalating immune response. Symptoms caused by cytokine storms are myriad, ranging from flu-like symptoms to rashes to low blood pressure to hemorrhaging to liver and kidney failure, just to name a few.
There are still a lot of unanswered questions surrounding cytokine storms. Covid-19 is not the only virus to trigger them; they’ve been observed in several severe infections from influenza to herpesvirus to the bubonic plague. It should be noted that pathogens which cause such severe infections often have defenses against the complement system, from bacteria secreting proteins which disable complement proteins to viruses using an infected cell's own defenses against complement to protect itself. Coronaviruses appear to have similar complement evasion abilities, though these aren’t perfectly understood, so it’s possible that the immune system has to hit harder to fight a resistant virus, meaning those harder hits cause more collateral damage. A person’s propensity for cytokine storms with Covid are linked to the severity of the infections they experience, though like everything else involving individual Covid severity, very little is understood. With over 200 proteins involved in the complement system and cytokine signaling, there are likely numerous genetic variations that could give one a more or less hair-trigger immune system, though it could be a while before this is fully understood.
Fortunately, progress has been made. You might have heard of interleukin-6, one of the most important cytokines for signaling inflammation and immune responses. Early in the pandemic, it was found that the amount of IL-6 in a Covid patient’s blood correlated to how severe their infection would be, giving doctors and nurses information with which to prepare and triage. There are also drugs that can inhibit cytokine responses and reduce the severity of cytokine storms. How to use such drugs is an area of ongoing research, as weakening the immune system during an active severe infection is something one should do very carefully. This has understandably become an area of research with a lot of focus and will likely yield some useful insights into who is most at risk for severe illness (Covid or otherwise) and how to mitigate against this. Regardless, our immune systems are even more intricate and wondrous than we give them credit for.
For More Details
* Blood vessels are structured like a braid of hair with a hollow channel in the center of the braid. Blood flows through this hollow channel normally, but the braid can be loosened to create gaps for fluid and cells to move through.
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