Complement

MANNAN-BINDING LECTIN PATHWAY

(MBP or MBL) - initiated when lectins bind to carbohydrates on the surface of bacteria. These lectins have a domain that acts like C1 and activate C2 and C4. The rest of the pathway is similar to the classical pathway.

describe the control mechanisms of the complement system - REGULATION

Because activation of the complement cascade will result in death of most cells onto which the components are activated, it is important to regulate the process to help insure that bystander cells (e.g normal) are not destroyed This is done through a variety of regulatory proteins that relatively quickly inactivate the active components (I will not assess you on the material that has a "red" line through it).

describe the roles of the complement receptors

Complement receptors play an important role in helping us get rid of invading microbes. Some of the complement receptors help in opsonization and clearance of immune complexes (CD35 and CD11), some help in the activation of the B cell (CD21...remember, CD21 interacts with CD19)

BIOLOGICAL FUNCTIONS - repeated

Once activated, the complement cascade has various functions to help destroy the invading microbes The three major activities involved in destroying microbes: - CELL LYSIS (through the MAC) - stimulating INFLAMMATION (via C3a, C4a, and C5a) - stimulating OPSONIZATION (through binding of complement receptors to C3b or C4b) Complement can also help to get rid of soluble antigens by helping to remove immune complexes (e.g. antigen/antibody complexes)

detail clinical methods to assess complement activity, proteins, functions - MEASUREMENT

Patients with a genetic defect in one of the complement proteins will have LOWER complement activity Patients with diseases that result in immune complex formation will also have LOWER complement activity (e.g. lupus) The CH50 assay: - uses a patient's serum and when RBCs that have been coated with rabbit IgM are added to sheep blood, the cells should be lysed - If the concentration of patient serum required to lyse the RBCs is relatively high, it indicates that the amount of complement activity is lower than normal - The CH50 levels will often increase during an acute phase reaction due to increased production of the complement proteins during this scenario. The AH50 assay: - measurement of activation of the alternative cascade Measuring serum levels of C3 and C4: - can be used to monitor the status of patients with immune complex disease (e.g. lupus) - useful as a measure of monitoring treatment efficacy

describe the significance of the membrane-attack complex

The complement cascade can be activated by three different initiators: 1. antigen-antibody complexes activate the classical pathway 2. LPS and other bacterial products activate the alternative pathway and finally 3. bacterial sugar-binding molecules (lectins) can activate via the mannan-binding lectin (MBL) pathway No matter which pathway is used, they all end up with the membrane attack complex (MAC) resulting in lysis of the target cell

Complement proteins

The complement proteins: - can also play an important role in removal of immune complexes (somewhat similar to the opsonizing function) - there are about 30 - were originally named based on their discovery - Most are designated as a "C" with a number (ex. C1, C3) Upon activation of the protein, the protein is split into two parts: - larger part binding to the microbe/target cell - smaller part diffusing away Larger sub-unit= designated with "b" Smaller subunit is designated as "a" NOTE: This nomenclature is not consistent and the C2 component: C2a= larger and C2b = smaller. BUT some of the newer textbooks have switched the designation

define the role of the complement system in host defense - including cell lysis, opsonization, and inflammation

Upon activation, the complement cascade can result in microbe: - CELL LYSIS (through activation of the membrane attack complex) - OPSONIZATION of the microbe (through binding of C3b onto the microbe and macrophage complement receptor recognition) - INFLAMMATION (through the production of C3a, C4a, and C5a) Lastly, when a complex of complement proteins is enzymatically active, they have a "bar" written over them. For example, C4b2a is the active enzyme that cleaves the next component of the cascade (C3). Therefore, C4b2a is also called C3 convertase.

ALTERNATIVE PATHWAY

activated by the presence of "special" molecules associated with microbes WITHOUT the presence of antibodies. - Even without antibodies, innate system cells (e.g. macrophages) can recruit other cell types to help destroy the invading microbe The best studied activator of the alternative pathway is LPS but other cell wall components have been shown to activate the pathway as well (e.g. teichoic acid, components of fungi, and/or some viruses and protozoan parasites) In addition, the process starts by the spontaneous splitting of C3 → C3a +C3b - C3b can then bind to foreign microbes and with "special" cell wall components, the alternative pathway is activated - Although C3 is split spontaneously, it doesn't usually damage normal host cells because there are factors produced that inactivate C3b when it lands on normal cells As with the classical pathway, the alternative pathway will eventually form the MAC and lyse the target cell. NOTE: Text within red boxes is NOT fair game for my exams. This information was kept to show the complete pathways but I do not consider them high yield concepts worth remembering.

CLASSICAL PATHWAY

initiated when antibodies bind to their antigen on the surface of a cell - After antibody binding to its cell-bound antigen, the C1 component of complement interacts with the Fc region of an IgG or an IgM molecule - In order to be activated, C1 MUST interact with AT LEAST 2 Fc regions Given that IgM already has 5 Fc regions, a single IgM molecule can activate the classical pathway, whereas, AT LEAST 2 IgG molecules are needed Given that the IgGs need to be in close proximity to each other, the reality is that in order to activate via the classical pathway, their likely needs to be HUNDREDS of IgG molecules binding to the surface of the microbe in order to have two close enough to each other for one C1 to bind both Fc regions The C1 molecule is made up of 3 different subunits with C1q binding to the Fc region of the antibody and afterward, there is activation of C1r which activates C1s. Upon activation, C1s can then activate both C4 and C2 (both of which are split and C4a and C2a float away while C4b and C2a bind to the surface of the cell) C4b2a = C3 convertase → cleave C3 into its active components: C3b which binds to the cell surface and C3a floats away. IMPORTANT MOLECULES: - C3b interacts with complement receptors on the surface of macrophages and C3a is an anaphylatoxin (can stimulate inflammation by causing degranulation of mast cells/basophils). - the interaction of C4b2a3b will activate C5. - C5a is another anaphylatoxin and C5b begins the MAC, resulting in C6 through C9 activation and formation of a pore within the surface of the cell → cell lysis