Complimenting the Complement System
Humans have evolved an elaborate system of immunological defenses against disease-causing pathogens. You may be familiar with T cells, B cells, and macrophages. Or perhaps you are aware of these cells more collectively as white blood cells. You may have heard of antibodies, which have been mentioned more frequently in the news these days as part of the diagnostic testing for COVID-19.
But you probably haven’t heard of the complement system. Even in grad school as an immunology student, the complement system was rarely discussed. And when it was, one could easily get lost in the convoluted naming conventions used to describe its key proteins. The complement system’s alphanumeric nomenclature, as we will briefly discuss below, could be easily mistaken for an inventory list at a Mercedes-Benz dealership.
While the complement system can sometimes be seen as a bit player in the immune system, it plays key roles in protecting us from things that try to make us sick. And unfortunately, like many processes in our bodies, if the complement system isn’t functioning properly, it can contribute to disease. This has led numerous companies to spend millions of dollars developing drugs that target complement signaling in disease.
So hopefully, by the end of this post, you’ll have a better appreciation of this often-overlooked component of our immune system.
What is the Complement System?
The complement system, more commonly just referred to as “complement,” is part of our innate immune system, the part of the immune system responsible for our initial defense against pathogenic invasion. Elements of complement can even be found in invertebrate species, all the way down the evolutionary ladder, indicating that complement is an ancient immune defense mechanism that has been conserved over time.
As part of the innate immune system, complement participates in the body’s early detection system for pathogens (immunosurveillance), as well as the rapid response to any threat. In general, complement plays a supporting role in these functions, “complementing” the activity of other immune cells and proteins (yes, this is how the complement system got its name).
While the complement system can trigger a range of outcomes, including immune cell activation, its best-known role is killing pathogens. The complement system is comprised of a variety of proteins that participate in cascades of events that predominantly lead to killing of the pathogenic cells, like bacteria. These proteins are organized into three main pathways: the classical pathway, the alternative pathway, and the lectin pathway. While the pathways share some complement proteins, they are activated by different stimuli and process the complement proteins slightly differently.
Generally speaking, for the classical pathway’s activation, antibodies (Y-shaped proteins that bind to specific patterns, or antigens) must first bind to a pathogen. The classical pathway then starts with the complement C1 complex. Part of the C1 complex, C1q, recognizes and binds the antibodies bound to the pathogen. This activates the other components of the C1 complex: a protein called C1r cleaves its neighbor C1s to activate it. C1s then acts as a molecular scissors to cut two more complement proteins, C2 and C4. In turn, the cleaved C2 and C4 interact to form another pair of scissors called the C3 convertase, which cuts a key protein called C3 into C3a and C3b. C3b then turns around and binds to the C2/C4 complex to form the C5 convertase, an alphanumeric monstrosity called C4b2b3b (or C4b2a3b, depending on which nomenclature system you’re using, and yes, I know that it’s confusing). As you may have guessed, this protein complex forms the final pair of scissors in this pathway and cleaves the next protein in line, converting C5 into two fragments. One of these parts, C5b, binds to the complement proteins C6, C7, C8, and C9. Thankfully, this collective complex has a more descriptive name – the Membrane Attack Complex (MAC). The MAC forms a pore structure in the pathogen’s cell membrane, poking holes in the cell to kill the pathogen.
The lectin pathway is very similar to the classical pathway, the key difference being the initiation event. Instead of relying on antibodies, the lectin pathway starts with the binding of sugar structures that commonly stud the surface of bacterial and other pathogens. Our body produces proteins called mannose-binding lectins (MBL) that bind to these sugar molecules. Once bound, the MBLs bind to proteins called MASPs, forming a complex that performs a similar function to the classical pathway’s C1r and C1s. The MASPs cleave and activate C2 and C4, leading to the same cascade seen in the classical pathway and resulting in the death of the pathogen by the MAC attack.
The alternative pathway, as its name would suggest, is slightly different. Unlike the classical and lectin pathways that have clear ON switches that depend on complement proteins binding antibodies or sugar molecules, the alternative pathway exists in a constant state of low-level activation. This hair-trigger state allows it to quickly respond to invading pathogens. The alternative pathway starts with a modified form of C3, called C3(H2O). When this form of C3 interacts with a protein called Factor B, it results in a C3 convertase. This complex is then able to cleave and activate additional C3 proteins. The resulting C3b proteins can bind directly to a pathogen’s surface and interact with Factor B to create additional C3 convertase complexes to create more C3b molecules, thereby rapidly amplifying the complement response. When the C3 convertase complex binds to another protein called properdin, it forms the C5 convertase and results in the same complement cascade that ends in the formation of the MAC on the pathogen’s surface.
Regulating Complement
While the details of the complement cascades can be convoluted and confusing, it’s clear that complement is an efficient way to detect and kill pathogens. Because of this ability, as well as its role in activating immune cells, it’s important that the system has regulators to ensure that the pathways aren’t mistakenly triggered. These regulators include proteins like complement Factor H, complement Factor I, membrane cofactor protein (MCP), decay-accelerating factor (DAF), complement receptor 1 (CR1), and CD59. In general, these proteins regulate complement signaling by accelerating the decay and degradation of the convertases. DAF and CR1, for example, can bind to C3b and prevent it from forming the C3 convertase. Factor H can bind to C3b and trigger its destruction by Factor I. These regulators play important roles in preventing the complement system from running wild and causing unnecessary inflammatory damage in our bodies.
Complement in Disease
Like many of the vital processes within our bodies, when things go wrong with the complement system, it can contribute to disease. In some cases, people can be deficient for a protein in the complement pathway. Due to the redundancies within the immune system, the impact isn’t always obvious, making diagnoses rare, but complement deficiency can lead to increased susceptibility to infection.
In other cases, issues with the complement regulators have been associated with disease. Without proper regulation, the complement system can become hyperactive, leading to increased inflammation and tissue damage. Genetic variants in complement regulators have been associated with the development of age-related macular degeneration (AMD), a serious retinal disease that leads to vision loss. While multiple influences are believed to contribute to the progression of AMD, genetic variants in complement Factor H and complement Factor I have been identified in subsets of AMD patients. Some of these genetic variants result in decreased levels of the protein, and it is thought that improper regulation of the complement system can contribute to disease progression. For this reason, there are multiple companies targeting complement as a treatment strategy for AMD. Gemini Therapeutics, for example, hopes to deliver functional Factor I and Factor H proteins into patients to restore proper regulation of the complement system. Other companies, such as Apellis Pharmaceuticals and IVERIC Bio, are targeting other points along the complement pathway, working to specifically inhibit C3 and C5, respectively. While these companies are progressing through their development plans, a previous attempt by the biotech behemoth Genentech at targeting the complement pathway failed, underscoring the complicated nature of the complement system in AMD.
Summary
In this post, I tried to cover the basics of the complement system and recognize the important roles it plays in keeping us healthy. As you might expect, the science of complement is far deeper than what I’ve covered here. As briefly mentioned above, the complement proteins do more than just kill pathogens. They also act as key signaling molecules on a variety of immune cells and provide key points of crosstalk between different immunological signaling pathways. Researchers continue to study these fundamental proteins and continue to build our understanding of how complement keep us healthy.
Thanks to Todd Festerling and QIAGEN for sponsoring the blog.