Research

In the balance. An introduction to the immune system

The purpose of our immune system is to protect the body from invading infectious agents such as viruses and bacteria (called ‘pathogens’). But there is a fine balance between providing this protection without overreacting and causing harm. The immune system is unbalanced in diseases such as rheumatoid arthritis and multiple sclerosis, and this is also thought to be the case in ME/CFS.

For the next few weeks our research posts will be focusing on the immune system in ME/CFS, with articles written by Dr Eleanor Roberts. She starts by introducing the components of immunity and how they act together to protect our body.

There is no single organ of the immune system. Instead it comprises several components throughout the body, including the thymus gland, spleen, lymph nodes, brain, blood, lymph and digestive system.

Immune-system cells arise from a single ‘stem cell’ type found in the marrow (inner part) of some bones, as shown in the diagram below.

Activation of the immune system can depend on both internal and external factors, including a person’s genes, meaning that one person can react to a pathogen very differently to another, both in the short and long term.

There are two main divisions of the immune system:

  • Innate immunity, which quickly protects against invading pathogens;
  • Adaptive immunity, which helps maintain long-term protection.

The innate immune system

The cells of the innate immune system can be divided into three groups:

  • Monocytes, including:
    • Macrophages, which are found in lymph nodes and tissues throughout the body. They eat and process pathogens and old cells of the body, and are involved in inflammation.
    • Dendritic cells, which are found in lymph nodes and tissues such as the skin, lungs and intestines. They process and present antigens to T-cells.
  • Granulocytes, including:
    • Neutrophils, which are the most common type of white blood cells. They kill pathogens by ‘eating’ them.
    • Basophils secrete chemicals such as histamine which are involved in inflammation.
    • Eosinophils are inflammatory cells which kill parasites such as worms.
    • Mast cells are involved in inflammation, and they secrete histamine and cytokines.
  • Natural killer (NK) cells instruct pathogen-infected or some cancerous cells to self-destruct.

Macrophages, neutrophils and dendritic cells can directly kill invading pathogens by engulfing them when they recognise parts of the invader as foreign. This is called ‘phagocytosis’, following which a dendritic cell breaks the pathogen into component parts and displays these on its cell surface.

Innate immune cells can secrete chemicals that attract more white cells to where they are needed (chemokines) and chemicals that cause an inflammatory response (cytokines). Inflammation occurs when chemicals are released following tissue injury. These chemicals are mostly released from mast cells and can lead to pain, swelling, redness and warmth, which can be localised to the tissue but also occur throughout the body.

Although NK cells are lymphocytes, they work within the innate immune system, for instance by producing cytokines so they can interact with macrophages and dendritic cells. NK cells are ‘patrol’ cells that check whether cells in the body are infected by a pathogen. All cells display ‘self’ signals (like an ID badge) that can be turned off if they are infected and will display a ‘foreign’ signal from a pathogen if it’s inside the cell. If either of these happen, the infected cells will be killed by the NK cell.

The adaptive immune system

There are two types of adaptive immunity:

  • Humoral immunity, where antibodies attach to a pathogen to stop it infecting a cell and to get rid of it;
  • Cell-mediated immunity, where cytotoxic T-cells recognise an infected cell in the body and kill it.

Adaptive immune-system cells are activated by a ‘foreign’ molecule, called an ‘antigen’, which is part of the invading pathogen that does not occur in the human body (e.g. a protein making up the outer coat of a virus, or a polysaccharide making up the cell wall of bacteria).

Antigens may also come from other sources, such as pollen, which triggers the immune system in people who have hayfever, and proteins called ‘secretoglobins’, which trigger the immune system in people allergic to cats.

The main cells of the adaptive immune system are the lymphocytes, which are carried in the blood and lymph (a liquid carried in the lymphatic system that can pass into tissues including lymph nodes) and can squeeze through gaps between cells to get into organs and tissues:

  • B-cells are made and initially develop in bone marrow, and they produce antibodies.
  • T-cells are made in bone marrow, and multiply and mature in the thymus gland. They include:
    • Helper T-cells (CD4+) which recognise specific antigens on a dendritic cell and bind to them creating a dendritic cell/helper T-cell complex, activating the T-cell to multiply and recognise that specific antigen. They also help B-cells produce antibodies.
    • Cytotoxic T-cells (CD8+) are activated when they bind to dendritic cells displaying pathogen parts as antigens. Once shown the antigen, the T-cell can recognise other antigen-displaying infected cells, which it can attach to and kill.
    • Regulatory T-cells (Tregs) supress other immune-system cells and cytokine production.

In adaptive immunity, the antigen is recognised by lymphocytes via special areas on the cell surface called ‘receptors’. When the antigen ‘key’ fits into the lymphocyte receptor ‘lock’, an immune response is triggered.

The diagram below illustrates how all these cells interact in the adaptive immune system.

Antibodies

Antibodies are a type of protein called an immunoglobulin (Ig) that are produced by B-cells. They can attach to a specific antigen (like a lock that only fits one key) and help stop a pathogen from infecting a cell in the body (‘humoral immunity’). While there are many types of immunoglobulins, there are four main players:

  • IgM is the first antibody produced on infection. It broadly suppresses a pathogen, but as IgM isn’t recognised by neutrophils, the pathogen won’t be killed by them.
  • IgG starts to be produced a few days following infection. It is targeted to a specific antigen.
  • IgA is found mostly in the lungs and intestines, and helps protect against, respectively, airborne and swallowed pathogens.
  • IgE binds to receptors on mast cells causing histamine and cytokine release, overproduction of which may lead to allergies (such as hayfever) and ‘mast-cell activation syndrome’.

Once produced, antibodies are first displayed on the surface of a B-cell as a receptor (the lock) for an antigen (the key). When the antigen docks with the receptor, both are taken inside the cell, the antigen is broken down, and its parts are displayed on the B-cell’s surface. This is why they are called ‘antigen-presenting cells’.

That B-cell then becomes an antibody-releasing cell known as a ‘plasma cell’. A single B-cell produces only one type of antibody, so future resistance to a pathogen develops when it multiplies.

On release, an antibody can bind to an antigen on a pathogen and help prevent the pathogen from being able to infect a cell, help neutrophils kill the pathogen, and help directly kill the pathogen by recruiting proteins called ‘complement’.

Some mature B-cells (memory B-cells) don’t turn into antibody-releasing cells but stay being able to recognise the antigen.

Working together

The innate and adaptive immune systems often work together. For instance, T- and B-cells can patrol the body via blood and lymph. When they enter the tissues and lymph nodes where dendritic cells live, they check to see if these cells are presenting any antigen, and, if so, the T- or B-cell can then ‘mature’ and there is an immune response.

Cytokines

Signalling between immune-system cells can also involve proteins called cytokines, which cause the target cell to react in a specific manner. Types of cytokine include interferons, chemokines, tumour necrosis factors, interleukins and the transforming growth factor beta family.

Different cytokines have different roles. For instance, some promote inflammation while some decrease it. Cytokines are usually only produced when needed, so they can be problematic if continually released.

Next week, Eleanor explores some of the ways in which the immune system may be disrupted in ME/CFS.

For more information about the immune system, try the excellent BiteSized Immunology resource from the British Society for Immunology.