The Complement System Flashcards
___________ components leave the host extremely vulnerable to both infectious and autoimmune diseases.
Early
Biological Consequence of Complement Activation
Lysis of Ab- coated cells
Promoting Ab formation
Cell lysis and viral neutralization
Which complement components are deficient in recurrent Neisseria infections?
C5, C6, C7, C8, properin, Factor D
Deficiencies of the Alternative Pathway
Factors D and B
Factor D deficiency is
- very rare and has only been described in two families.
- Both of these families had multiple members with a history of serious infections.
Factor B is an acute phase protein and increases during inflammation.
•There is only one unconfirmed report of this deficiency in humans.
The tickover pathway is rapid and, once the ALPW has been initiated, more than_______________ molecules of C3b can be deposited on a microbial surface in less than 5 minutes.
2X 106
MAC is a doughnut-shaped structure with a ____________ exterior that allows association with the pathogen membrane. Its internal ___________ channel acts as a pore in the lipid bilayer and results in loss of ______________ and eventual destruction of the pathogen.
hydrophobic; hydrophilic; membrane integrity
Deficiencies of the Lectin Pathway Components
MBL, M-ficolin, L-ficolin, H-ficolin, CL-11, MASPs
- Serious pyrogenic (fever-inducing) infections in babies and children.
- found w/ a frequency 2 to 3 times higher in SLE patients than in normal subjects.
MBL is not a primary immunodeficiency
Three pathways of the complement system
Classical: antibody-antigen complex
Lectin: Lectin binding to pathogen surfaces
Alternative pathway: Pathogen surfaces
Deficiencies of the Alternative Pathway
Factor Properdin
- Properdin is the only CM protein that is X-linked.
- The protein is synthesized by monocytes, granulocytic cells and T-cells.
- Several mutant forms of the protein have been identified that result in decreased AP function.
- Properdin deficiency increases the susceptibility to bacterial infections of the Neisseria family of organisms.
- The most prominent in the group is N. meningitis, the cause of a serious form of meningitis.
- Typical family histories include male relatives who have had or died from Neisserial infections.
What role does the complement system play in triggering infection?
- C3a, C4a, and C5a act to stimulate smooth muscle contraction and increase vascular permeability.
- C5a and C3a bind to receptors on mast cells and basophils, and induce the release of pro-inflammatory mediators, such as histamine.
- When present at a high level, these complement fragments are involved in a generalized circulatory collapse termed anaphylactic (anaphylatoxins).
- Treated with epinephrine (adrenaline) shot ASAP
C3 is cleaved into C3a and C3b. What does C3a do?
binds to receptors on basophils & mast cells triggering the release of histamine (anaphylatoxin)
What role does CR1 play?
- Increases uptake of Ag by antigen-presenting cells
- Can help provide secondary signals to B cells for activation and increase their uptake of antigen to present to helper T cells
- Can help to stimulate T cells to release cytokines, further potentiating innate inflammatory and adaptive immune responses
•Patients with a deficiency in properdin production are uniquely susceptible to ______________induced by the _____________ bacterium. These findings suggest that properdin has the capacity to act as a ______________, specifically directing the activation of the alternative pathway onto the surface of Neisseria and other microbial cells.
meningococcal disease; Neisseria gonorrhoeae; pattern recognition receptor (PRR)
What bond is formed when C4 is cleaved? What effect does this have?
A thioester bond is exposed.
- This bond is reactive, binding to amino groups on the surface of a target
- If no target is present, the bond is quickly hydrolyzed and rendered inert
Which complement components are deficient in asymptomatic?
C9
What are the major components of the classical pathway?
C1 through C9, which are inactive until they are cleaved
the first lectin demonstrated to be capable of initiating CM activation
Mannose-binding Lectin
The Alternative Protease-Activated Pathway
- Thrombin cleaves C3 and C5 in vitro with the release of the active anaphyltoxins C3a and C5a
- Plasmin is capable of generatin both C3 a and C5a
- Platelet activation releases ATP, Ca2+ and serine/ threonine kinases that could stabilize C3b in fluid space
This indicates that strong inflammatory reactions could potentially activate CM systems
Which complement components are deficient in Immune complex disease?
C1q, C1s, or C1r2s2, C2, C4
Which complement components are deficient in recurrent pyogenic infections?
C3, factor H, factor I
How does the complement system mediate the interface between innate and adaptive immunities?
- Increases uptake of Ag by antigen-presenting cells
- Can help provide secondary signals to B cells for activation and increase their uptake of antigen to present to helper T cells
- Can help to stimulate T cells to release cytokines, further potentiating innate inflammatory and adaptive immune responses
How is the Complement System Regulated?
- Dissociation of C1 complex, prevents cleaving of C4 and C2
- Decay-accelerating activity for C3 Convertases (Accelerates the decay of C3 convertase and Factor H binds C3Bb to make it accesible to be cleave by Factor I
- Regulation by catalytic activity (Factor H binds C3Bb and serves as a cofactor for the cleavage of surface bound C3b by Factor I. CD46 binds either C3b or C4 promoting inactivation by Factor I. Cd46 functions to limit C3 and C5 Convertase activity.
- Inhibition of lysis by MAC via protectin (CD59), vironection, and S protein
- Cleavage of anaphylatoxins (removes arginine residues from the carboxy termini of C3a and C5a via carboxylpeptidase
Contraction phase is also known as ____________
terminating phase
Classical Complement Pathway (CCPW)
- Part of the __________immune response
- It is initiated by ___________
- C1 becomes activated when it binds to an ____________
- Only complexes formed by ___________or certain subclasses of __________Abs are capable of activating the CCPW
- potent activators:_______ and ________
- poor activators: ________ and __________
adaptive
Ab binding
Ag-Ab Complex
IgM; IgG
IgG1 & IgG3
IgG2 & IgG4
Steps of the Classical Pathway
- C1q binds antigen-bound antibody, and induces a conformational change in one C1r molecule, activating it. This C1r then activates the other C1r and the two C1s molecules.
- C1s cleaves C4 and C4b binds to the membrane close to the C1. C4b binds C2 and exposes it to the action of C1s. C1s cleaves C2, creating the C3 convertase, C4b2a.
- C3 convertase hydrolyzes many C3 molecules. Some combine with C3 convertase to form C5 convertase.
- The C3b component of the C5 convertase binds C5, permitting C4b2a to cleave C5.
- C5b initiates the generation of the MAC
The alternative pathway is considered to be a part of the _________- immune system.
Innate
Less than _________ molecules of IgM bound to a RBC can activate the CCPW and induce lysis, whereas some __________molecules of cell-bound IgG are required to ensure the same result.
10; 1000
CM components constitute ~ __________% of the globulin protein fraction in plasma, and their combined concentration can be as high as _________mg/ml
15;3
4 main functions of the Complement system
- Triggering inflammation- C3a, C4a, and C5a trigger inflammation
- Attraction of immune cells
- Opsonization
- Pathogen lysis
Characteristics of MBL
Binds close-knit arrays of mannose residues that are found on microbial surfaces such as:
- Bacteria strains: Salmonella, Listeria, Neisseria
- Fungi strains: Cryptococcus neoformans, C. albicans
- Viruses: HIV-1 & RSV (respiratory syncytial virus).
Components of the C1 macromolecular complex. How does a stable interaction occur?
- one molecule of C1q
- two molecules each of the serine proteases: C1r and C1s
* held together in a Ca2+ stabilized complex (C1qr2s2)
C1q globular heads must be bound to two Fc sites
Additional initiators of the LPW of CM activation
L-ficolin,
H-ficolin, and
M-ficolin
- each bind specific types of carbohydrates on microbial surfaces.
Which complement components are deficient in andioderma?
C1 inhibitor
•Paroxysmal Nocturnal Hemoglobinuria (PNH)
- “PNH Thrombosis”
- Pancytopenia
- with Nocturnal build up of dark urine
- Coombs negative Hemolytic anemia (complement-mediated)
- venous Thrombosis
- rom pro-coagulant and pro-inflammatory state formed by complement activation
- May cause
- aplastic anemia (pancytopenia)
- myelodysplasia
- acute leukemia
- Defect in glycosylphosphatidylinositol (GPI) anchors DAF (CD55) and Protectin (CD59) on RBC membrane
- these protect RBC from complement
- DAF inhibits C3 convertase
- CM-mediated destruction of RBCs
- activation of platelets and WBCs
- Clonal stem cell defect from mutation in hematopoietic stem cell
- Somatic mutations in the X-chromosomal gene PIGA
The ALPW is initiated in three ways:
A.The Alternative Tickover Pathway
B.The Alternative Properdin-Activated Pathway
C.The Alternative Protease-Activated Pathway
The Alternative Properdin-Activated Pathway
- Properdin binds first and initiates the Complement on the membrane
- C3b and Factor B are then recruited
- Factor D is recruited to cleave Factor B
- C3bPBb complex acted as an effective C3 convertase
- Breakdown of C3b generates a fragment (__________) that binds to Ags
- enhancing their uptake by dendritic cells and B cells.
- The C3d-Ag complex binds to the same receptor on B cells that the _____________uses to gain entry into B cells
- where it may cause mononucleosis and,
- sometimes, ____________.
C3d; Epstein-Barr virus (EBV);Burkitt’s lymphoma
•Most CM components are synthesized in the _____________.Some are produced by other cell types: ____________
liver by hepatocytes
blood monocytes, tissue macrophages, fibroblasts, and epithelial cells of the GIT and GUT.
CM proteins
a set of serum proteins that cooperates with both the innate and the adaptive immune systems to eliminate blood and tissue pathogens.
C1 esterase inhibitor deficiency
- leads to uncontrolled CM activation
- •a complex disorder: hereditary angioedema (HAE):
- excessive production of vasoactive mediators (molecules that control blood vessel diameter and integrity),
- leads to tissue swelling and extracellular fluid accumulation
- suffocation can occur if the airways are obstructed, and
- the acute swelling of the abdominal region produces intense pain often resulting in exploratory surgery.
Acute treatments
- C1 inhibitor,
- a replacement therapy (both plasma derived and recombinant products are available);
- Prophylactic treatments include attenuated androgens and C1 inhibitor.
What role the complement system play in promotion of opsonization?
- Phagocytic leukocytes, including neutrophils & macrophages, carry receptors for C3b (CR1).
- When an antigenic particle is coated with C3b, C3b (also C4b) assists in the adherence and ultimate ingestion of the particle by the phagocytic cell.
- Opsonized microbes easier to ingest/destroy
- Opsonized immune complexes easier to clear
- The C5a fragment also enhances phagocytosis by stimulating phagocytic cells to ingest C3b coated Ags
What role does complement system play in clearance of immune complexes?
Clearance of Immmune complexes from the circulation depends upon C3b
Via C3b, Ag-Ab complexes bind to complement receptors on circulating RBCs
As the RBCs pass through the spleen and liver, the coated complexes are stripped off of the RBCs by resident phagocytes
Deficiency in the process can lead to renal damage due to accumulation of immune complexes
C5 is cleaved to C5a and C5b. What does each component do?
•C5a is a potent anaphylatoxin and a chemotactic attractant for neutrophils
C5b serves as the anchor for the assembly of a single molecule each of C6, C7 & C8 and activates MAC.
Role CR2 on B cells
•Binds to C3b on opsonized
bacteria/antigens
•Helps provide secondary signals to B cells through
BCR complex for more
efficient activation
All three pathways of the complement system function to:
- Recruit inflammatory cells
- Opsonize pathogens
- Kill pathogens
The Initiation of the Alternative Tickover Pathway of CM
- C3 undergoes spontaneous hydrolysis at its internal thioester bond, yielding the molecule C3 (H2O)
- Factor B binds to C3 (H2O)
- Factor B becomes susceptible to cleavage by Factor D. It cleaved to Ba and Bb.
- Ba is diffused away and Bb binds to C3 (H2O) in plasma, forming fluid phase C3 convertase
- Fluid phase C3 convertase cleaves C3 to C3a and C3b
- C3b binds to factor B on the microbial cell surface
- Factor B is cleaved by Factor D
- Membrane bound C3 Convertase is formed (C3bBb)
- The unstable membrane bound C3 Convertase is stabilized by Properdin
- Addition of another C3b molecule to the C3bBb complex forms the C5 convertase, which is also stabilized by Properdin
Lectin Pathway Steps
- Lectin recognizes microbial antigens and bind to the surface via lectin rectors
- MASP-2 on the surface of the microbial antigens cleaves C4 and C2 to form the C3 Convertase (C4b2a)
- C3 convertase hydrolyzes many C3 molecules. Some combine with C3 convertase to form C5 convertase
- The C3b component of C5 convertase binds C5, permitting C4b2a to cleave C5.
- C5b initiates the generation of the MAC
Alternative Pathway Control Proteins
Deficiencies of ADF & H Factors
- Deficiencies of factor H Decay-accelerating (DAF) activity for C3 convertase are linked with a wide variety of symptoms:
- leads to uncontrolled activation of the AP, and depletion of C3 occurs.
- Bacterial infections
- Deficiency or dysfunction of factor H and the resulting dysregulation of the AP is associated with various forms of
- kidney disease including atypical Hemolytic Uremic Syndrome (aHUS),
- as well as age-related macular degeneration (AMD).
