Lecture 2.2 Immunological reactions of organism.
Plan:
1. Complement: A Versatile Backup System
2. Overall Stages in the Complement Cascade
3. Specific Immunity: The Adaptive Line of Defense
4. An Overview of Specific Immune Responses
5. Development of the Immune Response
6. System Cooperation in Immune Reactions to Antigens
7. The Role of Antigen Processing and Presentation
8. B-Cell Responses: Activation of B Lymphocytes: Clonal Selection, Expansion, and Antibody Production
1. Complement: a Versatile Backup System
Among its many overlapping functions, the immune system has another complex and multiple-duty system called complement that, like inflammation and phagocytosis, is brought into play at several levels. The complement system, named for its property of “complementing” immune reactions, consists of at least 26 blood proteins that work in concert to destroy a wide variety of bacteria, viruses, and parasites. The sources of complement factors are liver hepatocytes, lymphocytes, and monocytes.
Complement functions as a positive feedback loop or cascade reaction. Its primary action is a sequential physiological response like that of blood clotting, in which the first substance in a chemical series activates the next substance, which activates the next, and so on, until a desired end product is reached.
Three different versions of the complement pathways exist (figure 1). Their main distinguishing features are how they are activated, major participating factors, and specificity. The end stages of all three converge at the same point and yield a similar end result, that is, destruction of a pathogen. The classical pathway is the most specific, activated mainly by the presence of antibody bound to microorganisms. The lectin pathway is a nonspecifi c reaction of a host serum protein that binds a sugar called mannan present in the walls of fungi and other microbes. (Proteins that bind carbohydrates are called lectins.)
The alternative pathway begins when complement proteins bind to normal cell wall and surface components of microbes. Note that because the complement numbers (C1 to C9) are based on the order of their discovery, some factors are not activated in numerical order.
2. Overall Stages in the Complement Cascade
In general, the complement cascade goes through four stages: initiation, amplification and cascade, polymerization, and membrane attack. The starting reaction requires some type of initiator molecule such as antibodies, lectins, or microbial surface receptors (figure 1 a), depending on the pathway. The presence of this initiator on the pathogen’s membrane propels the chain of actions involving complement chemicals C1 through C4, with each step serving a dual purpose. We are omitting the fine details of the amplification part of the complement system, but the end result is a molecule, C3, that is a key factor in subsequent polymerization and membrane attack for all three pathways. C3 is acted on by a convertase enzyme that gives rise to C5b, which forms the recognition site and anchor for the final series of reactions (figure 1 b). These amplification reactions also release cleavage products that serve other immune functions, including viral neutralization, allergic reactions, and immune regulation.
The final events in the complement series involve polymerization of C5b, C6, C7, and C8 into a half circular formation within the membrane (figure 1 c). This is followed by the insertion of several C9 molecules that complete a full ring-shaped polymer termed the membrane attack complex or MAC (figure 1 d). The MAC is the primary destructive force of the complement system. It effectively perforates and lyses the membranes of gram-negative bacteria, fungi, parasitic protozoans, and enveloped viruses. Except for the classical pathway, these reactions are non-specific and can be active against a wide spectrum of microbes.
Figure 1. Overview of the complement pathways. (a) All three pathways have different triggers and starting points, but they all converge at the same place, C3 convertase. This enzyme begins the series of reactions (b, c, d) that give rise to the membrane attack complex characteristic of the complement “machinery.” The final result is the formation of tiny openings in the cell membrane and the destruction of the target pathogen.