Complement Cascade -Thrush Flashcards
What are the four main functions of complement?
- cell lysis (due to MAC-membrane attack complexes)
- opsonization of Ag –> C3a and C3b bind to antigens and to C’ receptors on host defense cells–> increase phagocytic cell recognition and destruction of Ag
- mediates inflammation (anaphylatozins) (C3a, C4a, C5a): degranulation of mast cells, basophils and eosinophils, release of neutrophils from the bone marrow, increase expression of C’ receptors on neutrophils
- removal of immune complexes
Where are the complement proteins predominantly made?
By the liver cells
in some liver failure pts, will see more infections because of a decrease in the amount of complement proteins produced by the liver
What activates the classical pathway of complement?
The classical pathway is initiated when antibodies bind to their antigen on the surface of a cell.
After antibody binding to its cell-bound antigen, the interaction of C1 with at least TWO Fc regions of antibodies [IgG and IgM]
interaction ONLY occurs if there are multiple Fc regions in close proximity to C1
–> a single IgM can initiate classical pathway (because it has 5 Fc regions)
need 2 or more IgGs on a cell to activate classical pathway
What does C1s activate in the classical pathway of complement activation?
C1s then activates C4 and C2 (both of which are split and C4a and C2a float away while C4b and C2a binds to C4b–> C4b2a).
What is the function of C4b2a? What is produced and what do these products stimulate?
C4b2a is C3 convertase. This will cleave C3 into its active components: C3b which binds to the cell surface and C3a floats away.
C3b interacts with complement receptors on the surface of macrophages (C4b2a–> C5 convertase)
C3a is an anaphylatoxin (can stimulate inflammation by causing degranulation of mast cells/basophils).
The interaction of C4b2a3b (C5 convertase) will activate C5. C5a diffuses away (anaphyatoxin) and C5b binds to the target cell and begins the MAC, resulting in C6 through C9 activation and formation of a pore within the surface of the cell (causing cell lysis).
What activates the alternative pathway of complement?
NOT antibodies
LPS is the best studied but other cell wall components that are foreign to the host can as well. Ex: teichoic acid from some bacteria, components of fungi, and/or some viruses and protozoan parasites
What is the first step in the alternative pathway of complement? What is the last step in alternative pathway and what is the end result?
the process starts by the spontaneous splitting of C3 into C3a and C3b. C3b can then bind to foreign microbes and with “special” cell wall components, the alternative pathway is activated.
The last step: C5b binds to antigenic surface and then to MAC–> cell lysis
What activates the MBP (lectin) pathway of complement?
the pathway is initiated when lectins (proteins that bind to carbohydrates, ex: MBP) bind to carbohydrates on the surface of bacteria. These lectins (MBP) have a domain that acts like C1 and activate C2 and C4. The rest of the pathway is similar to the classical pathway.
What are the 3 main complement receptors? What do they bind to? Where are they located? What are their main functions?
- CR1 (CD35) erythrocytes, neutrophils, monocytes, lymphocytes (binds C3b, C4b)
- transport and opsonization of immune complexes
- RBCs bind immune complexes (containing C3b or C4b) and carry them to the liver and spleen/macrophages “grab” the complexes for destruction: RBC goes back into circulation - CR2 (CD21) – B cells (binds C3d, iC3b)
- uptake of immune complexes and B cell activation
- important in memory B cell activation (binds B cell co-receptor) - CR3 (CD11) – monocytes, neutrophils, and NK cells
- uptake of immune complexes, opsonization function (iC3b)
- binding can regulate cytokine production (IL-12 and IFNg from Mf….determine Th1 vs Th2 response)
What is the merge point for all 3 complement activating pathways?
C3
What is the most important level of control in C’ pathway? Why is regulation of Complement important?
C3!!
regulation of complement is important because it will result in the death of most cells onto which the components are activated –> want to ensure normal cells are not destroyed
What are six common ways that microbes evade the complement cascade and how?
- Gram neg. bacteria that have long-chain polysaccharides to LPS (strains of E. coli and Salmonella)
- ->prevent insertion of MAC - Gram neg. bacteria with certain outermembrane proteins
- ->MAC interacts with outermembrane protein and not cell membrane (strains of Neisseria gonorrheae) - Bacteria that produce elastase (Pseudomonas aeruginosa)
- ->inactivates anaphylatoxins (inflammation) - Gram + bacteria with thick peptidoglycan layer
- ->MAC does not efficiently get to cell membrane - Gram + bacteria with capsule
- ->capsule is a barrier between C3b deposited on cell membrane and CR1 on phagocytic cell
- ->decrease opsonization
- ->in order to lyse encapsulated bacteria, usually need C3b and Abs - Microbes that produce mimics of C’ proteins
usually inhibitory
ex. Vaccinia virus, HSV, EBV, Trypanosoma cruzi, Candida albicans, etc.
What are the 3 main complement receptors? What do they bind to? Where are they located? What are their main functions?
- CR1 (CD35) erythrocytes, neutrophils, monocytes, lymphocytes (binds C3b, C4b)
- RBCs bind immune complexes (containing C3b or C4b) and carry them to the liver and spleen/macrophages “grab” the complexes for destruction–> immune clearance - CR2 (CD21) – B cells (binds C3d, iC3b)
- uptake of immune complexes and B cell activation
- important in memory B cell activation (binds B cell co-receptor) - CR3 (CD11) – monocytes, neutrophils, and NK cells
- uptake of immune complexes, opsonization function (iC3b)
- binding can regulate cytokine production (IL-12 and IFNg from Mf….determine Th1 vs Th2 response)
Which Fc domain binds to which Ig domain in order to produce a classical pathway complement response? What is activated?
C1q binds to the CH2 domain of Ig.
Upon binding, C1r activates C1s
What are the two complement protein subunits normally called? What happens to each of these when activated (big picture)? What is the exception to the naming of subunits?
The larger sub-unit (typically “b”) normally binds to the target cell and the smaller subunit (typically “a”) tends to diffuse away and is important in stimulating inflammation .
C2a is actually the larger subunit and C2b is the smaller
