In today's blog I'm going to discuss three matters: 1) additional consequences of complement activation (other than drilling holes in bacteria); 2) ways that the complement system is regulated; and 3) hereditary disorders associated with defective complement components. To enliven matters, I'll briefly rant about the cost of trying to read journal articles on line. I'll also tell you about another book that I purchased. Here goes.
When a bacterium becomes covered with C3b (the larger of C3's two proteolytic cleavage products) as a result of activation of the complement cascade, specific receptors on macrophages and neutrophils recognize the ornamented microbe and allow these white blood cells to bind to the invader and "swallow" it up (phagocytosis). At the same time, the small proteins released by cutting C3 and C5 (C3a and C5a, remember?) act as cytokines to stimulate the inflammatory response, activating cells on the inner walls of capillaries. These endothelial cells increase expression of the protein selectin, thereby attracting neutrophils to the area via a mechanism discussed in a previous post. The neutrophils, in turn, may be stimulated sufficiently that they produce a series of powerful poisons that can kill bacteria (and if left unchecked, surrounding cells).
Another cellular player in the innate immune system, one which I haven't mentioned as yet, the mast cell, is also stimulated by these cytokines. It produces substances (histamines, if you must know) that cause blood vessels to swell and become more permeable, releasing plasma and blood cells into the surrounding tissue, thereby causing swelling and redness. Activated complement also interacts with the adaptive immune system, a topic that I'll get to in a future post. All these functions of complement, in addition to its ability to kill intruders by boring into their membranes, make complement a powerful force for defense against microbes. So powerful that it must be carefully regulated so that it doesn't get out of control.
One reaction that you don't want is to have the complement cascade activated so that it kills or injures normal cells. What's more, once a bacterial or other microbial invasion has been arrested, you'd like the complement reaction to stop. These two tasks are the concern of a dozen or so proteins, some of which circulate in the blood, others are located on the surface of cells. One of the most important of the complement regulators acts to break up the C3Bb complex. Another interferes in the last part of the cascade to block the formation of the apparatus that pokes holes in the membrane of bacteria. The others function at the early step in all three pathways of complement activation to limit the proteolytic cascade. Some of these regulatory proteins are found on the surface of almost all normal cells, thereby protecting them from attack by complement, limiting complement action to non-self cells. Mutations in the genes for some of these regulatory proteins result in several disorders including age related macular degeneration. For those of you who want to dive into the depths of the subject of complement regulation (and for a more detailed overview of the complement process in toto), I recommend this article by Marina Noris and Giiuseppe Remuzzi. It's not meant for beginners, but I found it less technical than others that cover the same subject.
If I give you the impression that everything is known about complement, you would be mistaken. Of course, a lot is known, and I haven't even pierced the skin of the subject. But my impression is that in coming years, much more will be learned and therapies that take into account the complement system will increasingly be important clinically. As of today, the impact of the defects in the system on disease can be best summarized in the following table taken from a review article by J. Vidya Sarma and Peter A. Ward. It provides a good summary of the major disorders associated with defects in the complement system.
Since the table contains many terms that I haven't covered, let me help interpret. The fifth row indicates that defects in complement's main components, including C3, C5, and C6 to 9 (ones that I've described) results in a susceptibility to meningitis (caused by bacteria of the genus Neisseria). Gonorrhea is another disease that is caused by an organism in the same genus and people with defects in these same components are also susceptible (not shown in the table). Another serious and common illness is lupus (as indicated in the row above). It is often associated with defects in the major components of two of the other branches of the complement system. Most of the other deficiencies in the table are in regulatory factors. They generally cause an increased susceptibility to infections of various sorts.
While other human disorders have been reported to be associated with defects in complement, they tend to be rare and, when they do occur, often resolve themselves without too much harm. To my mind, and remember, this is from an uninformed source, that may be the consequence of two factors. First, it may be that the human body is very good at compensating for defects. That in turn may arise from the fact that many physiological systems are redundant, and backups may come into play in the event of a deficit somewhere else. Second, it may be that we don't know enough about how complement acts. Subtle health issues may arise from problems associated with the complement system and we may not be aware of them. To that point, several articles that I've come across have hinted at a role for complement in Alzheimer's Disease, atherosclerosis, and cancer. Look out for news concerning the association of complement and these and other disorders in the future.
Now for a rant. I've presented references to two review articles above. Both are available on the web for free. But for many other articles, access is restricted and there's a charge to read them, sometimes a considerable one. As it happens, I can access almost all papers of interest gratis because I am an Emeritus Professor at Rutgers. The position entitles me to few benefits (no salary is one), but it does allow me to utilize the University library system to read journals that the library subscribes to on line. Since Rutgers is a major research university, it has to subscribe to almost all the important journals.
But what about my students? What about physicians? What about ordinary people who want to explore a subject in depth? They'll have to pay, sometimes $10 or more per article. Or they could subscribe to the journal. But subscription costs are extraordinarily high for many journals, so high that only major libraries can afford them. The publishers claim that these fees are justified, but my understanding is that journal publishers have an extraordinarily high rate of return on their investments, higher than almost any other industry. In response to the high cost of subscriptions, many "open-access" journals have appeared. I hope that this trend continues.
One last item. I've obtained another general reference, a short soft cover book. It's called "The Innate Immune System: A Compositional and Functional Perspective" by Tom P. Monie of Cambridge University. So far I find it well written, up to date, and a little less technical than the text by Abbas et al.