Complement

I must admit that having a following is giving me an excellent impetus to finish some of the content that I keep promising but, for reasons relating to school and all of the hundreds of other things I am doing right now, just don't get to in as timely a fashion as I want.

Last time we were talking about C3 convertase, an enzyme that is made differently by each pathway, but each pathway does, in fact, make it.

What differentiates the pathways, I should mention, is how each pathway is activated. The classical pathway is activated by interaction with Immunoglobulin G and M that have interacted with antigen. How that comes about will be the topic for another discussion. The lectin pathway reacts with a sugar that is often found on the coats of pathogens known as mannose. The alternative pathway spontaneously forms the C3 convertase, unlike the others which are triggered by the above interactions, but the difference is that unless there are certain molecules on the pathogenic membrane (lipopolysaccharides, glycoproteins, etc.) to interact with, the C3 convertases break down and don't do anything.

A side note: immune diseases are caused when these kinds of molecular interactions either don't take place or the control mechanisms preventing the immune system from functioning in the absence of pathogens are faulty. Some nasty diseases can be caused if complement goes haywire or doesn't function.

The classical pathway takes longer to respond because it is a little dependent on all of the processing and presentation that happens in order to get IgG and IgM that have been exposed to antigen. However, the alternative pathway is extremely fast. My immunology professor said that it reacts in a matter of minutes, whereas other parts of the immune system can take days to respond.

Once the C3 Convertase is achieved, still more reactions occur and still more cleavages of proteins occur in cascade fashion until a C5 Convertase is made. All 3 pathways make C5 Convertase, which is important to make a molecule of different complement proteins called a Membrane Attack Complex, or MAC. It is thought that the MAC physically punches holes in pathogenic membranes, lysing the cells by doing damage to the cell wall.

Typical of biology, systems are made to be efficient and minimize waste (well, except for B and T cells) and complement is no exception. In the progressive cascade involving cleavages of different proteins and the creations of enzymes that help make the final product, the cast off bits of proteins have important immune functions of their own. The lectin and classical pathways create molecules that are important for the inflammatory response, useful for heating the local tissue in order to make the areas inhospitable to pathogens. They synthesize molecules that make the epithelium of capillaries leaky, allowing fluid into the tissues and helping to bring in other cells that are important for immune responses like macrophages, neutrophils, mast cells and basophils. They even make proteins that can help macrophages and neutrophils phagocytize pathogens by 'marking' them for destruction. Complement proteins also create anaphylotoxins, implicated in anaphylaxis or severe allergic reactions because of signaling molecules that induce mast cells and basophils to dump their granules full of histamine. Histamine is important in inflammation, as a protective measure. Too much of this, or inappropriate reactions, can cause anaphylactic shock. Anaphylaxis can be fatal.

I hope you enjoyed my discussion of complement. It is a very lengthy topic, and breaking it down to simple terms was challenging. But I think I'm getting the hang of this, and I had fun doing it. I would like to talk about blood moving through the heart and differential pressures at some time today.

References:

Janeway’s Immunobiology, 7^th edition by Murphy, Travers, and Walport. Garland Publishing, 2008

Medical Microbiology, 6^th edition by Murray, Rosenthal, and Pfaller. Elsevier/Mosby, 2009

University of South Carolina School of Medicine