The Humoral Immune Response Flashcards
B cell activation
The B cell receptors recognise the antigen on the surface of a pathogen. But at the same time B cells will need help from the T cells.
So they will engage with the T helper cells through the MHC molecules.
But also the antigen for the T cells could be different of that recognised by the B-cell receptor. So the B cells and the helper cells are not going to have the same specificity, but they will be able to interact.
This will lead to further differentiation of the B cells into plasma cells, and these will be able to secrete the antibody.
The antibody will be acting in different ways:
- Neutralisation - preventing bacterial adherence;
- Opsonisation - increased phagocytosis;
- Complement activation - enhances opsonisation and lysis of some bacteria.
The T-helper cells that activate the B cells are the T-FH cells.
When an antigen engages through a helper cell, we call it a thymus-dependent antigen.
The first signal for the differentiation of the B cell is given by the cross-linking of the B cell receptor with the antigen. The second signal is provided by the helper T cell in the form of cytokines.
But some antigens can provoke antibody production without the help of a T cell. These are called thymus-independent antigens, and they have a rapid response, because it doesn’t go through the different activation stages from the helper cells.
Here the B cell does it all on it’s own. The first signal is the cross-linking of the receptors in an indirect way, and the second signal is given by the activation of the innate immunity receptors like the TLR.
B-cell proliferation (or clonal expansion)
Cell proliferation means amplification of the cell that is able to engage with the antigen, so that they will be able to produce antibody.
Then later we have the differentiation of resting memory cells and antibody-secreting plasma cells.
Antigen presentation to the B cell
As the B cell binds a virus through a viral coat protein, there is going to be a receptor mediated endocytosis, where the virus particle will be internalised and degraded.
Then the virium can be processed into peptides, which can now be loaded into MHC molecules. Then the helper cell can engage with the B cell.
The antigen will be different for the recognition by the B cell and the processed peptide recognised by the MHC molecule, but they both come from the same pathogen. This is called a linked recognition - same pathogen, different epitope.
Then the helper cells release a second signal, which are the cytokines for the activation of the B cell. Then the B cell transforms active proliferation into a plasma cell that can release the antibody, which can further neutralise the antibody.
T cell engagement with the B cell
The way a T cell will engage with a B cell is through an immunological synapse. In the periphery, there are going to be molecules for adhesion, which are leukocyte functional antigens and ICAMs, and in the centre there is going to be the specific interaction with the MHC molecules, the peptide and the T cell receptor complex.
Then when we have these specific interactions ongoing, the components of the cytoskeletal granules of the T cell will be driven towards the immunological synapse.
So in that sense we will make sure that the granules of the T cells containing cytokines are going to be released and will activate only the B cells they are engaging with, and not the ones in the follicles in the lymph nodes.
Activation of B cells leads to a decrease in SIP expression.
In the first signal, the B cells will be able to interact with the antigen present in the periphery. Then, there are going to be T cells able to engage with the activated B cells, to deliver the second signal. Here, those B cells will move from the follicle away, and they will produce a primary focus. Primary focus appears after 5 days of infection, and there are going to be plasma-blasts. The plasma blasts are able to release antibodies early during the immune response.
Not all the activated B cells will become plasma blasts, some of them will return to the follicle for further differentiation into plasma cells. The cells that return will undergo somatic hypermutation, and will make a better antibody.
Antigen presentation to the dendritic cells
There are different ways:
1) free antigen can get there and get trapped by the macrophages located there. They will not internalise the antigen, they will just trap it into the membrane and the follicular helper cells will also be trapped in the membrane, so the B cells can engage with the antigen that way.
2) engage with the antigen present in the membranes of the macrophages.
B cell movement
The B cells will enter the lymph nodes through the high endothelial venules.
If they are not activated, they will leave the lymph node, through the efferent lymphatics and recirculate in the lymph, in different lymph nodes.
The B cells will be in the circulation because they make it easier to get to the site of infection quickly, and engage multiple sites.
If the naive B cell enters the lymph node and is activated by antigen, then we are going to see the primary focus, but some cells will return and produce a germinal center.
Here, the plasma cells will migrate to the medullary cords or leave via the efferent lymphatics and will home to the bone marrow. In the bone marrow they can leak out the antibody, which will go into the circulation into the site of infection, since there will be inflammation and will be driven by it.
In the germinal center, we have the centroblasts in the middle, on the outside we are going to have centroytes. Centroblasts and centrocytes are B cells in different processes of differentiation. The germinal cells will be made 3-4 weeks after the antigen exposure.
The centroblasts and centrocytes are going to be attracted to a particular cytokine, then they will stop expressing the receptor, and will be attracted to another chemokine. Here the cell are undergoing a somatic hypermutation. After that they will be moved on the outer part of the cell and will engage with the T cell. If the receptor that they produce was good, then they get a lot of activation with the T cells, and they go back inside and engage the receptor again. So if they get activated, they will have multiple rounds of somatic hypermutation.
The cytokines released by the helper cells not only go for somatic hypermutation, but also for class switching.
Different cytokines can induce or inhibit the expression of different isotopes of antibodies.
Thymus independent antigen
There can be two types:
Type 1 (low concentration):
There will be an antibody specific response because the available concentration is more likely to be there for antigen specific response.
Type 1 (high concentration):
There will be a polyclonal B-cell activation, and there will be a nonspecific antibody response, because other immune receptors, like the TLRs can activate them, and that’t enough for the B cells to produce antibodies. Not all polyclonal B cells will be unspecific.
Type 2:
Here we will need a repetitive epitope, so the cell can release IgM. In the case when there is a dendritic cell, presenting the repetitive epitope to the B cell, the dendritic cell releases cytokines that will induce class switching in the B cells, and will result in a different class of antibodies for the thymus antigen type 2.
But there is not going to be somatic hypermutation.
Antibody activity
- IgG4 is good for opsonisation and neutralisation, and it can make hybrid antibodies, meaning that the antibody can be bivalent, with two distinct antigen specificities.
- IgM is good for neutralisation, opsonisation and complement system activation;
IgM is present in circulation. - All IgGs are important in neutralisation, opsonisation , complement system activation and sensitisation of mast cells and Nk cells;
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IgG is the major Ab in the blood, in circulation - IgA is good for neutralisation, opsonisation and complement activation.
IgA will be present in the mucosal tissue as a dimer, and it will have a specific receptor - polymeric immunoglobulin receptor.
That is going to be present in the vasolateral membrane of the epithelial cell in the gut.
The plasma cells in that area will release antibodies. The antibodies will bind to the receptor, and will have receptor mediated endocytosis, the vesicle will move all the way to the surface and releases the antibody. Now the antibody is located in the mucosal tissue. In there it can neutralise toxins produced by the pathogens, or even the pathogens.
The IgA will be present in the gut, respiratory tract and lactating breasts. - IgE is important for sensitisation of mast cells.
The mast cells are in the connective tissues and they contain a lot of granules. They can bind antibodies through receptors, specifically and best IgE. When the IgE molecules will be cross-linked by the antigen, the cell will degranulate. The granules contain pro-inflammatory mediators, but also molecules that will promote the contraction of the smooth muscle, which will have different function depending on the tissues, like coughing, sneezing, or vomiting.
IgE is located in the connective tissue.
The brain and the uterus do not have antibodies present, because they are immuno-privileged sites, meaning that they have their own barriers. Like the brain has the brain-blood barrier, and the uterus will have these sites during pregnancy, like the placenta. These will prevent pathogens to enter those areas.
- IgD is for regulatory functions.
Toxins
Toxins are released by the pathogens, and they have a structure similar to other cellular receptors, so they can bind those receptors.
Then we have endocytosis, where the toxin will be activated, and they can damage the tissue. Antibodies can neutralise toxins, because when they bind to them, they prevent the toxins fro binding to the receptors.
Antibodies have a function called passive immunisation, meaning that we have the intending use of the antibody to prevent death. If we get a strong toxin into the body, we can get a shot of antibodies directly that will act on the toxin, this is different from vaccine immunisation, because there we inject a small amount of antigen to produce antibodies, which happens in a period of time. Passive immunisation is for immediate action.
With passive immunisation, there is no antibody memory.
Once the antibodies bind the toxins, they will form complexes that will be processed by complement system opsonisation. Then the bigger complexes can bind the erythrocytes which have receptors for the C3b and as it circulates it can drag this mass, and get the complex with the toxin to the spleen or the liver, which will process them.
If they are not processed they will block some organ functions.
The FcRns are receptors in the organs that will accumulate those complexes. They are present in the gut, liver, and endothelial cells, as well as different granules of the immune cells and mast cells.
Viruses and bacteria
For a virus it is important to bind the cell, so it can be internalised and divide in there. But if we block those receptors using antibodies, they will not be able to do their function.
Some viruses have sialic acid residues, which allow them to bind different saccharides on proteins or lipids in our cells, so it is important that we have antibodies against those residues.
The bacteria is going to bind to the surface of the cells, and they can be internalised, where they will produce a cytosolic infection. So neutralising them with antibodies helps preventing then to bind anything in our body.
