Complement system Flashcards
Where are the complement proteins made?
Liver
What are the 3 pathways for complement activation?
Classic
Alternative
Lectin
What will activation of complement proteins do?
When activated, the complement protein will recruit inflammatory cells,
perform opsonisation and kill pathogens
Complement triggers the following immune functions:
1: Phagocytosis – by opsonizing antigens. C3b has most important opsonizing activity.
2: Inflammation – by attracting macrophages and neutrophils-c5a and c3a
3: Membrane attack – by rupturing membranes of foreign cells (C5b, C6, C7, C8 and polymeric C9)
4. clearance of the immune complexes by phagocytes
What activates the classic pathway?
The classical pathway is usually initiated by
antibodies bound to antigens, forming what is called immunocomplexes.
Both the IgM and IgG antibody isotypes are capable of initiating complement activation. It takes two units of IgG or one unit of IgM to trigger complement activation. The most efficient antibody for this purpose is the IgM’s which are pentameric in structure (composed of 5 single antibody subunits).
This type of morphology is excellent for activation of the classical pathway, as the 1st complement component of the classical pathway is the C1 component, which is composed of 3 subunits, C1q, C1r and C1s (just remember QRS as in ECG)
The C1q subunit is a hexameric protein complex with 6 globular heads, all of which are able to bind to a Fc region
of the pentameric IgM molecule. The C1q subunit has to connect to at least 2 Fc regions in order to activate the C1
component, and since IgM’s have 5, they are excellent C1 activators. When the C1q has bound to the appropriate number of Fc regions, it allows the C1r and C1s subunits attach to the C1q subunit, forming the complete C1 component
Following binding is the formation of the c1 complex which then generates c1s esterase, an enzyme capable of cleaving inactive proteins c4 and c2 into their active forms (c4a and c4b, and c2a and c2b respectively)- The activated c2b and c4b fragments form a protein complex (C2bC4b complex) called c3 convertase (which is different from the one formed through the alternative complement pathway).
CRP is also capable of activating the classical pathway imitating the FC region of the antibody and calling upon c1q
What activates the alternative pathway?
It is initiated by the spontaneous hydrolysis of C3, which is abundant in the blood plasma. “Tickover” occurs through the spontaneous cleavage of the thioester bond in C3 to form C3b(H2O).This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb.Bb remains bound to C3b(H2O) to form C3b(H2O)Bb. This complex is also known as a fluid-phase C3-convertase.
This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds properdin, a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase.
**Properdin is required to stabilize the c3bBb convertase
What activates the lectin pathway?
In contrast to the classical complement pathway, the lectin pathway does not recognize an antibody bound to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars.
When the MBL binds to the pathogen/bacteria, it
recruits other enzymes just like the C1q
component in the classical pathway. These
recruited enzymes are called Mannole-binding
lectin Associated Serine Protease (MASP)
enzymes.
Together, the MBL-MASP complex functions as
an enzymatic complex that recruits and cleaves C2
and C4, which ultimately results in the formation
of a C2bC4b complex on the surface of the
pathogen (same as classical c3 convertase)
Ficolin can ALSO activate the lectin pathway by binding to N-actetylglucosamine
What are Mannose-binding lectin?
MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition (a soluble PRR) in the first line of defense in the pre-immune host. MBL recognizes carbohydrate patterns, found on the surface of a large number of pathogenic micro-organisms, including bacteria, viruses, protozoa and fungi. Binding of MBL to a micro-organism results in activation of the lectin pathway of the complement system.
What are the components of the membrane attack complex and what does it do?
The membrane attack complex (MAC) is a structure typically formed on the surface of pathogenic bacterial cells as a result of the activation of the host’s alternative pathway, classical pathway, or lectin pathway of the complement system, and it is one of the effector proteins of the immune system.
The membrane-attack complex (MAC) forms transmembrane channels. These channels disrupt the cell membrane of target cells, leading to cell lysis and death
Active MAC has a subunit composition of C5b-C6-C7-C8-C9 (10-16 molecules in a pore forming structure)
What forms the C5 convertase and what does it do?
Bound C3b then complexes with its original “C3 Convertase” to form a “C5 Convertase”. Therefore, when activated by the Classic or MB-lectin pathway, the C5 convertase is composed of C3bC2bC4b whereas when activated by the Alternative Pathway, the C5 convertase is composed of C3bBb3b.
The “C5 Convertase” cleaves circulating C5 into C5a and C5b. C5b then initiates the generation of the “Membrane Attack Complex”.
- The C3b component can either bind to the surface of a pathogen where it recruits factor B in order to from an alternative C3 convertase, it can also bind to the pathogen alone, or it can attach to the pre existing convertases on the surface of pathogens (either to the classical [C2bC4b] or to the alternative [C3bBb] C3 convertase)
What is the function of C3a
C3a’s roles in innate immunity, upon binding C3aR, include increased vasodilation via smooth muscle contraction, increased vascular permeability, and mast cell and basophil degranulation of histamine, induction of respiratory burst and subsequent degradation of pathogens by neutrophils, macrophages, and eosinophils, and regulation of cationic eosinophil protein migration, adhesion, and production.
C3a is also able to play a role in chemotaxis for mast cells and eosinophils, but C5a is a more potent chemoattractant. C3a also plays an important role in adaptive immunity, moderating leukocyte production and proliferation
Whats the function of C5a and C5b?
C5a is an anaphylatoxin, causing increased expression of adhesion molecules on endothelium, contraction of smooth muscle, and increased vascular permeability. C5a des-Arg is a much less potent anaphylatoxin. Both C5a and C5a des-Arg can trigger mast cell degranulation, releasing proinflammatory molecules histamine and TNF-α. C5a is also an effective chemoattractant, initiating accumulation of complement and phagocytic cells at sites of infection or recruitment of antigen-presenting cells to lymph nodes. C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of integrin avidity, the lipoxygenase pathway and arachidonic acid metabolism. C5a also modulates the balance between activating versus inhibitory IgG Fc receptors on leukocytes, thereby enhancing the autoimmune response
C5b: This step is the last enzymatic cleavage step, as the C5b component is not an enzyme, instead, it is able to bind to the surface of pathogens where it recruits other complement components, including C6, C7, C8 and many C9 components. Together, these components can form the membrane attack complex (MAC)
Function of C3b
Opsonization (enhance phagocytosis by 4000x)
C3b components deposited on the surface of pathogens functions as opsonins (recall that C3b components can bind alone to the surface of pathogens). When C3b is deposited on the surface of a pathogen, they can be recognized by complement receptors present of the surface of phagocytic cells like macrophages (CR1) - important in opsonization.
Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B (C3bBb complex), or a C5 convertase when bound to C4b and C2a (C4b2a3b complex) or when an additional C3b molecule binds to the C3bBb complex (C3bBb3b complex).
In addition to labelling pathogens, C3b components are also able to bind to theFc region of AG associated IgG’s or IgM’s (they can bind to the Fc region of AB’s which have labelled an antigen) In this way, the C3b componentsare able to facilitate phagocytosisof AB-AG immonocomplexes in the body This is useful as larger AB-AGimmonocomplexes often becomesinsoluble, and binding of C3b to the Fc region of the Ab’s causes dissociation of these larger complexes, forming smaller, soluble immunocomplexes.
At the beginning of the C3b degradation, iC3b components will be formed.These components are still active opsonins and can facilitate phagocytosiso Later, smaller components like C3d are formed. These components are unableto initiate phagocytosis, however, they are able to stimulate antibody formationby plasma cells, which are cells of the adaptive immune system.
Once cleaved C3b can either generate C3 or C5 convertases, as mentioned above, or else covalently bind to the microbial surface, tagging the cell for phagocytosis in a process known as opsonization. Additionally, C3b molecules can attach to the Fc regions of antigen-bound antibodies leading to phagocytosis or movement to the liver, where the C3b-tagged immune complex is then destroyed. In both cases C3b interacts with the C3b receptor, complement receptor 1 on phagocytic cells, such as macrophages and neutrophils, allowing for engulfment of the pathogen. Furthermore, erythrocytes with Cr1 on their surface bind and deliver the immune complexes to the mononuclear phagocyte system via interactions with C3b.
What are the different functions of the two complement receptors?
This co-operation occurs when an AG fits to a B-cell receptor (BCR), which can lead to B-cell activation. However, in order to initiate a proper B-cell response, costimulationis often requiredo One of these co-stimulatory signals comes from the Complement Receptor type 2 (CR2), which are also presenton B-cell so The CR2 are able to bind to C3dcomponents which are present on theAG, bound to the BCRo This generates a stronger B-cellresponse which result in a moreeffective AB synthesis and secretion(B-cell gets activatedtransforms intoAB secreting plasma cell)
Function of CR2 and what is the name of the disease associated with CR2 receptor?
CR2 (CD21) is involved in the complement system. It binds to iC3b (inactive derivative of C3b), C3dg, or C3d. B cells have CR2 receptors on their surfaces, allowing the complement system to play a role in B-cell activation and maturation.
CR2 on mature B cells form a complex with two other membrane proteins, CD19 and CD81(=TAPA-1). The CR2-CD19-CD81 complex is often called the B cell coreceptor complex,[6] because CR2 binds to antigens through attached C3d (or iC3b or C3dg) when the membrane IgM binds to the antigen. This results in the B cell having greatly enhanced response to the antigen
A disease associated with the CR2 receptors is infectious mononucleosis, more commonly known as the kissing disease. This is a viral disease caused by the Epstein- Barr virus which enters the body cells by binding to CR2 receptors
The virus is spread via saliva, and they first replicate within the epithelial cellsand later primarily within B cells, which causes an immune response towardsinfected B-cells, resulting in symptoms like enlarged spleen (splenomegaly)and enlarged lymph nodes
Function of complement receptor 1 (CR1)
Complement receptor type 1 (CR1) also known as C3b/C4b receptor or CD35 (cluster of differentiation 35.
Important for opsonization. E.g. in macrophages
Found on erythrocytes, leukocytes, glomerular podocytes, hyalocytes, and splenic follicular dendritic cells.
RBC- Bind immune complexes (by FC regions of IgM and IgG) and take them to the liver where they are picked up by phagocytes and cleared.
Phagocytes- Binding of complement-opsonized microbial cells results in receptor mediated phagocytosis.
B cells- Mediated antigen uptake of c3b bound antigen, leading to its degradation in the B cell lysosomal system and subsequent presentation to T cells, making it a player in both adaptive and innate system
The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus and sarcoidosis
