From MathBIO
Complement Membrane Reactions
Introduction
Defense Mechanisms
The human body's immune system has a variety of defense mechanisms to protect against foreign contaminants, or pathogen. These mechanisms include both physical and biochemical defenses. The biochemical defenses are split into two categories: those defenses that are 'innate' or are not specific to any pathogen, and those that are adaptive, which are acquired over time and attack specific pathogens. Amongst the defenses of the innate immune system there is a cascade of biochemicals known as the complement system that attacks the surface of pathogens. It is the development and propagation of this system that is a focus of research with the mathematical biology group at CU Boulder.
Complement
The complement system is a collection of proteins that provides a non-specific defense against foreign elements inside the body. This collection of proteins remain in an equilibrium state that is unbalanced by the presence of a foreign particle. The activation of specific proteins in the system causes a chain reaction that results in one of two processes that identify and destroy the source of the imbalance. The first pathway, called the Classical pathway, results in the tagging of the pathogen for elimination by other parts of the immune system. The second, called the Alternative pathway, results in the pathogen accumulating complement proteins on its surface and eventually being destroyed by the structure they create. It is this second pathway that is the focus of our research.
Detection
In the body the liver produces the base protein of the complement system, C3. These C3 proteins can break apart spontaneously in water into two smaller proteins, C3b and C3a. This C3b and a protein to be mentioned, Bb, can serve as catalysts for this reaction. These proteins, C3b and C3a, can then reform naturally into C3, and they do so as part of the natural equilibrium of complement in the body. However, if a pathogen is present in the body, C3b can bind to the membrane of the pathogen. If this occurs the C3b, while attached to the pathogen body, can bind with another protein, factor B, to form the protein C3bB. This new complex is then cleaved into two portions called Ba and Bb. Bb remains on the C3b on the surface of the pathogen, a structure now called C3bBb, while Ba floats off.
An interesting characteristic of C3b is that its reactive site is highly reactive to carbohydrates. This mechanism was examined through the study of the interaction between C3b and zymosan, a yeast cell wall polysachride. The affinity of C3b for the carbohydrate reinforces the purpose of C3b to identify and bind to pathogenic membranes.
It is important to note that the spontaneous split of C3 into C3b and C3a is a necessary component of the complement system. The low level supply of C3b allows for the initial necessary deposits to be formed on the pathogen membranes.
Activation
The C3bBb complex, now attached to a pathogen, serves as a catalyst and rapidly breaks apart free floating C3 proteins into C3a and C3b. This renews the detection cycle and results in a positive feedback loop that deposits large quantities of C3bBb on the surface of the pathogen.
The presence of C3bBb and C3b also allow for a larger structure, C3bBbC3b to form. This protein can split apart another protein of the complement system, C5, into C5a and C5b. These proteins initiate a cascade of reactions that result in C6, C7, C8, and C9 proteins forming a large structure together, called the membrane attack complex (MAC). The MAC complex forms on the surface of a pathogen and once it is large enough, it 'punches a whole' into the pathogen. This allows for lysis of the pathogen as the the whole thats created by the MAC allows for free diffusion to occur from between the inside and the outside of the pathogen.
Regulation
The primary component of complement regulation is that of Decay Accelerating Factor (DAF). DAF is a glycoprotein which exists on the membrane surface of the cells of the body. DAF causes the rapid decay of C3bBb, essentially removing the C3bBb from the surface of the cell by breaking it apart and allowing it to reform into C3. This allows for bodily cells to defend themselves from attack by preventing the initial deposits of C3b from growing and in turn fueling more deposits.
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