Next Lesson - Sepsis
- What are the key players in the adaptive immune response?
- What is the function of antigen presenting cells?
- What is MHC and why is it important?
- Why are T-helper cells important and how do they respond to intracellular and extracellular microbes?
- Antigen-presenting cells activate different T-lymphocytes and B-lymphocytes to help fight against invaders
- MHC is a series of proteins that the adaptive/acquired immune response needs to recognise foreign material
- Naïve T-cells differentiate into cytotoxic T-cells and several T-helper cells (Th1, Th2, Th17) which have different responses depending on the current active infection
To understand this article, we advise that you read the Innate Immune Response, or have a rough understanding of it.
Whereas the innate response is rapid, doesn’t have any memory of previous infections and cannot change the intensity of its response, the adaptive immune response is quite the opposite. So why does the adaptive immune response not start immediately fighting bacteria on infection?
While the innate immune response is holding the early front line against the invaders, the adaptive response is waiting for its cells to become activated. Certain types of cells, called antigen presenting cells (APCs), are floating around your body waiting to bind to foreign antigens that they do not recognise. Some examples of APCs include macrophages, dendritic cells, Langerhans cells, and B-lymphocytes.
An antigen presenting cell, eg. a macrophage will phagocytose a foreign pathogen, as part of the innate immune response. After taking it in and degrading it in lysosomes within the macrophage cell, a small sample of the antigen from the pathogen would then be displayed ("presented") on the surface of the macrophage via a molecule called a Major Histocompatibility Complex (MHC). Binding between the antigen-displaying MHC on the macrophage surface and a T-lymphocyte is what activates the T-lymphocyte; it is the requirement for this specific antigen-antibody binding that causes a delay in the adaptive immune response which becomes activated. Once the T-lymphocytes are activated, both activate B-cells to produce specific antibodies through cytokines, as well as beginning to proliferate and starting to mount their own attack against the invading pathogen. We’ll come back to T- and B-lymphocytes, as we need to discuss how the APCs do their job.
Presentation of antigens is classified by the major histocompatibility complex. What the MHC consists of is a set of cell surface proteins that are split into two main classes (there is a third, but it isn’t as important as the first two). In humans, the MHC is classified based on the human leukocyte antigens (HLAs) it expresses.
There are two main classes:
MHC class 1 molecules bind to T-lymphocytes (specifically cytotoxic T-cells, aka T-killer cells) via CD8+ receptors. Although it’s not essential to know, the main HLA proteins of the MHC responsible for this are HLA-A, HLA-B, and HLA-C. Only intracellular microbes (eg. a virus which has entered the cell) are presented via MHC class I molecules.
MHC class II molecules are only found on antigen presenting cells. Once an APC processes the antigen, it puts a little piece of it (called the epitope) on its cell surface along with a class II molecule. These APCs can then bind to the CD4+ receptors on naïve T cells (those that have matured from the thymus but not been activated before i.e. bacteria the body has not fought before) which differentiate into T helper (Th) cells. There are different types of T-helper cells - what determines the fate of each naïve T-cell are the co-stimulatory proteins (cytokines) that also bind to the naïve T-cell. The three most important types of T helper cell are Th1, Th2, and Th17. Both intracellular and extracellular molecules can be presented via MHC class II molecules.
Key facts about MHCs:
- The MHC molecules have a broad specificity so that a single cell can present multiple antigens from the same microbe to increase the immune response.
- Which specific HLA molecules are present on a person's MHCs determines their susceptibility to certain infections e.g. a HIV positive individual with three specific HLA molecules is more likely to have a slowly progressing disease with an effective T-cell response. This is genetically determined and explains why some people can be immune to certain diseases.
- A mismatch in MHC molecules between a donor and recipient in an organ transplant can cause rejection (known as Graft vs Host disease).
- Having certain MHC molecules can predispose individuals to certain autoimmune conditions e.g. insulin-dependent diabetes mellitus.
A helpful way of remembering which class of MHC binds to which CD receptor is:
When you multiply the MHC class and CD number together you should get 8:
MHC Class 1 binds to CD8+ (1x8)
MHC Class 2 binds to CD4+ (2x4)
Fighting off intracellular microbes - MHC class 1
An intracellular organism, for example a virus invading a cell to take over its replication machinery, can infect any cell. For this reason, MHC class 1 is expressed on all cells.
An APC can present both MHC class 1 molecules (as can all cells), as well as MHC class 2 molecules (specific to APCs) - this called cross-presentation and allows the APC to deal with both intracellular and extracellular pathogens (which it phagocytosed).
So, you’ve got an APC (eg. a macrophage) with its epitope (the part of an antigen molecule to which an antibody attaches itself) bound to an MHC molecule which has rocked up to a naïve T-cell – now what?
If that APC happens to be expressing the epitope in a MHC class I molecule, this will be bound by a T cell expressing the CD8+ receptor, leading to the activation of a cytotoxic T-cell. This ‘killer’ cell then goes off and kills any cells that have gotten inside body cells and infected them (e.g. a virus replicating inside a normal body cell).
What if that APC also had an MHC class II molecule that binds to the CD4+ receptor on a T-cell? Well in the case of intracellular molecules, the naïve T-cell that binds to the CD4+ will differentiate into a Th1 cell. This will then go on to activate B-cells and macrophages. The B-cells will produce specific antibodies which will bind go and bind with infected cells and pathogens in the body - they have a special protein on their surface called the Fc protein which is what macrophages can bind to so that they can phagocytose the pathogen (this is Fc dependent phagocytosis).
Fighting off extracellular microbes - MHC class 2
So now you’ve got an APC with an MHC class II molecule on it, which binds to the CD4+ receptor on T-cells. These are going to differentiate into Th2 and Th17 cells.
Th17 just has one action we need to know, and that is activating neutrophils by interleukin (IL) 17.
Th2 cells have a few different responses:
- Increases the number of eosinophils to help kill parasites (via IL-5)
- Activates B-cells to produce antibodies (for phagocytosis) and complement (via IL-4)
- Activates mast cells which are responsible for local inflammation and our allergic reactions (via IL-4)
A quick summary so far
- This fights off intracellular microbes such as viruses, bacteria, and protozoa
- Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen
- The receptors and cells involved are CD4+ differentiating naïve T-cells to Th1 cells and CD8+ differentiating naïve T-cells into cytotoxic T-cells
- Attack mechanisms are complement, macrophages, and cytotoxic T cells
- This fights off extracellular microbes such as fungi, bacteria, parasites, and worms
- Humoral immunity is the aspect of immunity that is mediated by macromolecules found in extracellular fluids such as secreted antibodies, complement proteins, and certain antimicrobial peptides
- The receptors and cells involved are CD4+ receptors differentiating T-cells into Th2 and Th17 cells
- Attack mechanisms are antibodies, complement, and phagocytosis
Primary and secondary immune antibody-based response
If you are unlucky enough to have had chicken pox, then most people would say that they only had it once in their life. This isn’t because once Varicella zoster invades you the first time, the body is able to destroy it before it causes disease the next time (the secondary immune response), since it has developed a memory against it. Once that horrible itchy period of chickenpox is over and you are healthy again, your body became a little savvy towards the virus when it was finally able to beat it off. Whenever you have hung around anyone else with the chicken pox, but never got it, it perfectly illustrates the difference between the primary and secondary antibody response.
The primary response is your body’s first response to a new pathogen that it has never encountered before. All that was mentioned above, with different cells needing to be activated, takes time so the virus is relatively untested against invading all the cells. The primary antibody produced against this response is IgM, which is less specific than an IgG reaction. It takes around 5-10 days for a peak primary immune response to be mounted, which is slow.
On the second exposure to the same pathogen, the secondary immune response is activated. This is primarily IgG and takes less time - usually 3-5 days to reach peak. This is a much faster and stronger response which also lasts longer than the primary immune response with IgM. These things combined with IgG’s high affinity for the pathogen, as the microbes enter the body you are already fighting away and preventing them from overwhelming your immune system (which is why subsequent infections as asymptomatic). This is also the basis behind vaccines and is illustrated in the picture below:
Figure: Shows the response of the adaptive immune system to a standard infection. The primary response on first exposure will be mainly IgM mediated. The secondary response on second exposure will be IgG (memory cells) as these activate more quickly than IgM. You will still get an IgM response in the secondary immune response.
Creative Commons Source Modified by Marcus Judge, Original by OpenStax College [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
The important thing to remember is that you won’t get a secondary immune response with the same pathogen unless the same antigens that were there during the primary immune response are present. An example where this is relevant is with the influenza virus. It has certain antigens, such as H aemagglutinin and Neuarminidase (which are also used to name certain flu strains, eg. H1N1), which are slightly different between flu strains. It is possible to keep getting the flu because the antigens are constantly mutating to different strains, and the flu vaccine is only for the most common strains at that particular time of the year.
Edited by: Marcus Judge
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