Innate immune system

What are the groups of white blood cells and why are there so many?

There are many different types of white blood cells; neutrophil, monocyte, eosinophil, basophil, B lymphocyte, T lymphocyte and natural killer cell. These are separate and evolved at different times, but cooperation between cell types is almost always needed. We need so many cell types due to the wide range of pathogens such as the very big (worms), the big (bacteria), the small and hidden (viruses), and the small and not hidden (toxins, initial virus exposure). 

How is each type of pathogen destroyed by the white blood cells?

Large organisms such as worms cannot be engulfed and digested, therefore cells need to cooperate and destroy them in the tissues whilst minimising the damage to normal cells. They are destroyed externally via immobilisation and release of proteins, which affects the surrounding tissues - a major role of eosinophils and basophils. 

Smaller organisms such as bacteria can be engulfed and digested safely by white cells without affecting the surrounding tissue. The main key is to do this quickly and effectively before the bacteria can cause damage and proliferate - a major role of neutrophils and monocytes. 

Viruses infect normal cells and replicate inside of them, therefore they are hidden from the immune system. The immune cells must recognise and destroy the infected cells whilst not affecting the normal cells - a major role of T lymphocytes and natural killer cells.

Specific proteins such as toxins or bacterial surface proteins may have a major effect on the body. The body must recognise and respond to these small antigens and ideally have memory if the antigen is encountered again - a major role of antibody secreting B lymphocytes.

How is COVID-19 detected and destroyed?

COVID-19 exposure can be detected using COVID-19 specific antibody levels in the blood. These antibodies prevent viruses entering cells and mark them for destruction by the immune systems. However, the T-cell response is also a major component of the immune response and may be more important in longer-term protection - Abs disappear.

What is the innate immune system?

This system has an ancient evolutionary origin. In some ways, the cells of the innate immune system appear to act in similar ways to free living organisms.

• It is useful to recognise the similarities between cells of the innate immune system and free living organisms such as amoeba – both face the same problems: They need to be mobile, interacting with and contacting other cells and recognising their features. They must be able to recognise non-self (prey) which they will attack, from self (other amoeba) which they must ignore.

What cells comprise the innate immune system and how do they recognise pathogens?

Neutrophils, eosinophils, basophils and monocytes recognise common proteins associated with infection. These are either the products of damage to the body (DAMPs - damage associated molecular patterns - released DNA…) or the products of bacterial infection (PAMPs - pathogen associated molecular patterns - bacterial surface proteins…). This is called pattern recognition by which non-specific receptors simply recognise things that should not be present.

What happens following pathogen recognition?

Once a pathogen is recognised, cytokines are released to help the formation, activation and early release of white cells from the marrow. These can be released from the damaged tissues or immune cells. For example, G-CSF will enhance the production and release of neutrophils, GM-CSF and M-CSF together can enhance the production of monocytes and granulocytes.

Additionally, at the affected site, there is a local inflammatory response caused by DAMPs and PAMPs which lead to the release of small chemokines which help recruit white cells to leave circulation and enter areas of inflammation. For example, CXCL8 or interleukin 8 which attracts neutrophils into inflamed tissues.

Both cytokines and chemokines may also cause cells to be activated to gain killing function. In the absence of infection, white cells need to be relatively inactive to reduce their potential for harm to normal tissues. For example, G-CSF increases neutrophil adhesion, granulation and responsiveness. The chemokine IL-8 can cause similar activation.

How is the innate immune response regulated?

There also needs to be a control mechanism to limit white cell responses;

• As DAMPs and PAMPs decrease since the cause of infection is killed, the production of cytokines in marrow and chemokines in tissue decreases. This reduces white cell production, reduces entry to infected areas, and reduces activation.

• Complete limitation of self-harm may not be possible as white cells use enzymes and other destructive molecules which allows them to kill pathogens irrespective of type. These also affect normal cells so must be balanced by mechanisms to avoid harm to tissues - each cell has their own method.

What are the characteristics of neutrophils?

At rest, neutrophils have a generally regular shape, with a multi-lobed nucleus (3-5) and finely granulated cytoplasm. They are highly motile cells that survive 12-24 hours in the blood, and a further 24-48 hours in tissues. Most neutrophils simply live out their lives without needing to fight infection - do nothing until stimulating to avoid damage to the body. Activated neutrophils lack a lobed nucleus, have Dohle bodies (enhanced synthesis of proteins/granules), have heavy granulation and glycogen stores for energy. These have enhanced adhesion and movement.

How do neutrophils kill pathogens?

Neutrophils engulf and kill bacteria inside themselves. They have adhesion receptors which adhere to bacteria, which are then engulfed into vacuoles called phagosomes, which fuse with the cell’s granules which digest them. The granules can be microbicidal such as myeloperoxidase, lysozyme or acid hydrolases (only work in low pH - inside vacuole), or iron-binding such as lactoferrin. This allows killing without damage to tissues. Neutrophils can release an extracellular DNA net trap as a last resort which traps bacteria in the local area until more neutrophils arrive.

For safety, the phagosome is internal so all killing is safely enclosed. The phagosome is often acidic inside and the enzymes from the granules work only in acid environments – this means they are fairly safe if they escape into the neutral environment of cells and tissues. The neutrophil at the end of its life must be safely disposed of – the process of apoptosis ensures that this happens – the neutrophil effectively releases enzymes internally that destroy all its toxic elements and prepare it for safe removal in the spleen.

What are the characteristics and roles of monocytes?

Monocytes are phagocytic cells with a range of functions. They have a generally irregular shape that is dynamically active contacting other cells or migrating. Their nucleus is kidney shaped/irregular, and they have a blue-grey cytoplasm which may contain fine granules. These spend around 17 hours in the blood before entering tissues where they become tissue macrophages.

The roles of the monocytes include; phagocytosis of bacteria, ‘wall in’ pathogens - join together to form a ring (granuloma) around a pathogen, and remove dead cells and promote wound healing. Their main function within tissues may be regarded as continuing the effects of neutrophils at a later stage.

What are the appearances of eosinophils and basophils?

Eosinophils have dense granules that generally do not overlie the nucleus, and when stained they appear red. Basophils have dense granules that overlie the nucleus, and when stained they appear blue. Both contain numerous granules that are released in tissues to destroy parasites.

What granules do eosinophils release?

The eosinophil granule contents include; 

• Histamine: dilates blood vessels allowing more blood cells to arrive, and causes swelling that traps invading organisms. 

• Contain multiple active proteins: Nucleases that break down DNA/RNA, Lipases that break down fat, Major basic protein attacks organism surface. 

• Potentially cause tissue toxicity as all these proteins may also damage tissues. When the parasite is destroyed, the activity of these cells is prevented particularly by helper T cells.

What granules do basophils release?

The basophil granules contribute to inflammation;

• Histamine (dilate blood vessels), serotonin (dilate blood vessels), heparin (prevents clotting), enzymes such as elastase that break down tissue matrix, and IL-4 (stimulates immune reactions, particularly IgE Ab release).

What are the inter-relationships within the immune response?

There are many inter-relationships between different components of this system.

• The innate system and the organism – you can see that the response to danger signals produced by organisms are proportionate to the level of threat (amount of danger signal) and time (duration of danger signal).

• Innate and the body – locally active factors such as cytokines and chemokines can be secreted by cells in a range of tissues - this links the immune system to overall health, but also allows responses to be localised to sites of threat.

• Innate and adaptive – although arising later in evolutionary terms, the adaptive immune system produces factors that influence the behaviour of the innate system providing extra control.

What happens when there are defects in neutrophils?

Since neutrophils are our first line of defence against bacteria, their deficiency can be associated with the development of persistent and often serious infection - often with pathogens that would not normally affect healthy individuals. Low number of neutrophils may be associated with an auto-immune disorder or chemotherapy. Defects may also lead to abnormal granules so they are unable to kill ingested bacteria. High numbers contribute to damage in inflammatory disease such as in rheumatoid arthritis.

What happens when there are defects in eosinophils?

High eosinophil numbers or excess granule release from abnormal eosinophils can lead to catastrophic damage as granules attack normal tissue. This can affect particularly heart valves leading to oedema, swelling and inflammation around the body. 

What happens when there are defects in basophils?

Inappropriate numbers or incorrect circumstances, the basophil granule content can be harmful. Abnormal reactions of basophils (and their tissue equivalent - the mast cell) are a major contributor in asthma. Allergens such as pollen affect the bronchi of asthma sufferers which causes release of granules and swelling around the small airways – as they constrict breathing becomes increasingly difficult. Drugs that stabilise are used to treat allergies.

What is a cytokine storm and what drugs suppress this?

In some instances, an immune response to infection becomes uncontrolled with cytokine and chemokine production causing excessive activation of inflammatory cells, causing the destruction of normal tissues that further increases cytokine release a ‘cytokine storm’. This provokes increasing uncontrolled inflammation.

• This is what is believed to happen in individuals severely affected by COVID-19, where the normal response to a viral infection by B and T lymphocytes begins to become uncontrolled, with increasing cytokine release that provokes inflammation due to inappropriate activation of the innate immune system. 

• The use of steroids (dexamethasone) at an early stage to suppress inflammation and prevent the cytokine storm progressing has made a major impact in the disease.