Abbas Chapter 8

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Abbas Chapter 8
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Abbas and Lichtman, Basic Immunology
Chapter 8 Summary
Author: Skylar Van Osch
Chapter 8 Summary
Effector mechanisms of humoral immunity
I like to keep my explanations simple, but comprehensive. I hope that you all find this useful and that there are few grammar/spelling mistakes. It will also be useful for you have reference the figures as you read - especially for the complement section.
-main function of adaptive immunity is preventing infection before it is established; only antibodies mediate this function. Antibodies can bind viruses when they are in the blood
Properties of antibodies that determine their effector functions:
Antibodies may function distant from their sites of production.
Produced by plasma cells in the lymph nodes
i. Enter the blood where they reach site of infection and also mucosal secretions
Also produced by plasma cells in the lamina propria of the GI tract
Protective antibodies are produced during the primary response and in larger amounts during the secondary response
Plasma cells may move to the bone marrow and produce antibodies for months or years
Memory b cells do not secrete antibodies until stimulated
antibodies use Fab (antigen binding) region to bind to and block harmful effects of microbes and Fc (constant) regions activate diverse effector mechanisms and eliminate their microbes and toxins
prevent harmful effects of microbes by binding them
Fc contains binding sites to activate phagocytes and the complement system.
i. Only activated if enough of the antibodies are bound by antigen
Functions of the different Antibodies:
IgG
Neutralization of microbes/toxins
Opsonisation
Activate complement
Antibody-dependent cellular cytotoxicity, mediated by NK cells.
Neonatal immunity
Feedback inhibition of B cell activation
IgM
Activated complement
IgA
Mucosal immunity
i. IgA is secreted into the lumen of GI/respiratory tract (later)
IgE
Defence against helminth parasites
Mast cell degranulation
Some other antibody properties/characteristics
there are neonatal receptors (FcRn) which are expressed in the placenta (more later) and endothelium.
In endothelium protects IgG from intracellular catabolism, and also prevents IgG from degradation due to lysosomes
Heavy Chain isotype switching – thoroughly covered in chapter 7
Results in the production of antibodies with distinct Fc regions, which enables the humoral immunity to engage in mechanisms that are optimal for combating specific microbes
Antibodies are active anywhere in the body
Microbial and Microbial Toxin Neutralization
Antibodies binds to and block/neutralize the infectivity of microbes and interactions of the microbial toxins with host cells
1. bind surface molecules/cell wall components of microbe
2. bind microbes that may be released from an infected cell
3. bind toxins and prevent other negative effects….
Opsonisation and Phagocytosis
antibodies coat microbes and promote their ingestion by phagocytes
opsonisation – the actual coating of a microbe, by opsonins, the molecules which coat the microbe and enhance Phagocytosis
if, for example, the antibodies are IgG1 and IgG3, their Fc regions bind to a high affinity receptor for the Fc regions of γ chains
the receptor is FcγR1; expressed on macrophages and neutrophils
the microbe is subsequently phagocytosed and the antibody/FcγR1 interaction activates the phagocyte to produce ROS, NO, and proteases in the phagosome
pneumococci (encapsulated bacteria) are only killed by this method
there are many more different types of FcγR (#) receptors, see Fig. 8-03
Antibody dependent Cellular Cytotoxicity
in this process, NK cells and other leukocytes bind to Antibody-coated cells and destroy them
NK cells express FcγRIII (CD16) which binds the antibody-antigen complex
As a result, NKs are activated to release the contents of their granules, which are proteins that kill the opsonised targets
IgE – and Eosinphil/Mast Cell-Mediated Reactions
IgE antibodies activate mast cells and eosinphil-mediated reactions that are important for helminth parasites and allergic disease
Helminth parasites are too large to be phagocytosed and are pretty thick which makes them resistant to microbial substances produced by macrophages and neutrophils
IgEs bind to the parasites and attract eosinphils via FcεR1
This receptor does not induce a cellular response, rather, neighbouring T cells secrete IL-5 which causes eosinphils to release granule contents which kill parasites
IgE also attracts mast cells whose CKs (cytokines) attract more leukocytes
Activation of Complement (THIS IS HEAVY…….. HAVE THE FIGURES OF THE TEXT BOOK HANDY….THEY WERE USEFUL TO WHEN GOING THROUGH THIS)
Complement is a collection of circulating and cell membrane proteins that are important in host defence against microbes and antibody –mediated tissue injury
GENERALLY (there is an exception) COMPLEMENT refers to the ability of these proteins to assist the antimicrobial activity of antibodies
This system is part of both the innate and adaptive immune responses. It may be singly activated by microbes or by antibodies attached to microbes
This is important: the activation of complement involves sequential proteolytic cleavages which generates specific protein fragments that help to participate in microbe elimination.
It achieves massive amplification because a small number of complement molecules may produce massive numbers of effector molecules
Activated complement proteins are become covalently attached to cell surfaces so that activation is limited to the correct site… (they don’t just move around activating whatever they touch…)
Complement is activated by three pathways
1) Alternative
2) Classical
3) Lectin
It is important to note that the C3 protein of the complement pathway is just chilling out in the blood and becomes randomly hydrolyzed to produce C3b. C3b is degraded really quickly. 
Also: all three pathways lead to the production of the C5 convertase complex. This doesn’t make sense to you now… but all of these pathways lead to the same thing…will explain once all of the ‘initiation’ pathways are explained..
Alternative pathway
Before C3b has a chance to get degraded, in runs into a microbe and forms a stable covalent bond with a microbial surface molecule… protein or polysaccharide
The microbe bound C3b becomes the substrate for the binding of Bb, which is a fragment of the protein B, broken down by a plasma protease
They form a C3bBb enzyme called C3 convertase which breaks down C3 to C3b (yes the same C3 from above). This is an “ALTERNATIVE” pathway for C3 conversion.
Many more C3bBb complexes are produced, and some bind additional 3b’s.
The now, C3bBb3b (love the b’s eh!!) is now a C5 convertase, which further initiates the microbicidal (I think this is a word?) functions of complement. I will get to this later
Classical Pathway
Triggered when IgM/B binds an antigen
Fc region is available for binding complement, however, 2 Fc regions must be close together for C1 (of the complement) to bind
C1 binds the Fc regions of the ‘close together’ antigen-bound antibodies and it becomes active.
Activated C1 results in the binding and cleavage of the complement proteins C4 and C2.
This results in the formation of the C4bC2b enzyme which becomes covalently bound to the microbial. The enzyme is called C3 convertase, which converts C3 to C3b. This is the “CLASSICAL” pathway for C3 conversion.
Like above, C3b binds with C4bC2b, and now the C4bC2bC3b complex is a C5 convertase.
Lectin Pathway
Initiated by plasma mannose-binding lectin (MBL) to microbe.
MBL is structurally similar to C1 (from above) and activates C4… the following steps are the exact same as the classical pathway
So from here, C5 is converted by all of the C5 convertase complexes formed above to C5b. C6, C7, C8, C9 then bind sequentially. C9 polymerizes to form a pore in the cell. This is called a membrane attackcomplex (MAC) and causes cell death. This is all outlined very nicely in the figures.
Functions of Complement
Microbes coated in C3b are phagocytosed as C3bs are recognized by type 1 complex receptor (CR1/CD35) on phagocytes
Opsonisation is the most important part of complement
MAC is only useful in microbes that have thin cell walls or little glycocalyx (an example is the bacteria Neisseria)
The fragments of C3/C4/C5
Chemotactic (attracts) for neutrophils
Stimulates release of inflammatory mediators for leukocytes
Acts on endothelial cells to enhance leukocyte motility
Complement also provides stimulus for the development of humoral response
Another breakdown product of C3 is C3d which is recognized by the CR2 receptor on B cells
This stimulates B lymphocytes (see chapter 7)
Complement proteins are also bound to Antibody/antigen complexes and are recognized by follicular dendritic cells. This allows for antigens to be displayed for selection of high affinity b cells.
Inherited C3 deficiencies are… bottom line.. not good
Regulation of Complement
Regulatory proteins that inhibit complement activation prevent complement from damaging host cells
Decay accelerating factor (DAF) disrupts binding of B to C3b, or C4bC2b to C3b
Membrane cofactor protein (MCP) is a cofactor for proteolysis of C3b into inactive fragments. This is mediated by a plasma enzyme called factor 1.
The type 1 complement receptor (CR1) is involved in both of the above mechanisms. (For example DAF and CR1 removed Bb and C4b from the C3 convertase enzymes
C1 Inhibitor (C1 INH) also stops complement early
Other regulator mechanisms at later stages… ie MAC formation.
Inherited diseases..
Decreased C1 INH produced hereditary angioneurotic edema. So there is over expression of C1 which = excessive protein fragments = edema
Paroxysmal Nocturnal Hemoglobinuria – defect in the anchor protein for DAF and MCP. Complement is activated on RBCs.
Antibodies function at special sites in the body
Mucosal Immunity
In the mucosa of the GI, IgA is produced by plasma cells in the lamina propria and actively transported through the epithelial cells by Ig A specific receptor. Receptor vesicle-mediated transport through the cell. In the lumen, a protease cleaves IgA with part of the poly-Ig receptor attached. The antibody is now free to bind any antigen. The polio virus is particularly dealt with this way.
Neonatal
Maternal antibodies are actively transported across the placenta to the fetus, and through the intestines after birth through breast milk.
Passive immunity
Both routes have the same receptor: FcRn
Microbe Invasion of Humoral Immunity
mutate antigen surface molecule
influenza, HIV, rhinovirus,
trypanosome parasite always changes its surface glycoprotein when it encounters an antibody it recognizes… this is why there are waves of infection
Inhibitors of complement
Resistance to Phagocytosis
Vaccination
Antigen/microbes are treated to abolish their infectivity and pathogenicity while retaining their antigenicity. These are called “attenuated” microbes.
They still stimulate antibody production and memory cell
Non-protein antigens are treated to contain a peptide so that helper T cells are activated and high affinity antibodies are produced
Conjugate vaccines
See Fig. 8-11 for a list of vaccines
It’s really hard to vaccinate from T-cell mediated antigens because it is tough to abolish the pathogenicity of intracellular antigens (viruses) while maintaining antigenicity.