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Do phagocytes need antibodies to be able to engulf pathogens (to function)?

Do phagocytes need antibodies to be able to engulf pathogens (to function)?


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I recently saw a question about monoclonal antibodies, that are specific to a certain virus, being split (into their constant and variable regions via an enzyme), and the question asked whether some statements were false or true.

One of the statements said that the virus could be engulfed by phagocytes if any were present. The statement turned out to be false and I'm not completely sure why. Is it because phagocytes need fully intact antibodies to function so that they can attach to them via receptors specific to the constant region of the antibodies consequently becoming attached to the virus and so being able to engulf it?

I thought that phagocytes could work on their own and that antibodies just made their job easier. Is that assumption correct?


Phagocytes don't necessarily need antibodies to recognize intruders, i.e. by presence of non-self sugars. Additionally, phagocytes can aid amplification of effective anti-bodies by presenting degraded pathogens to the adaptive immune-system. I found this concise summary of the innate immune system, that I would strongly recommend to read!

Now to your more specific question: Detection of viruses. You have to consider, that viruses are highly optimized to evade the innate immune system:

Viruses can happily replicate and mutate without proof-reading without negative consequences and with relatively low conceptual constraints, as they are so simple, compared to cells. This is why the innate immune-system is prone to miss viruses (at least those, that are optimized for a certain species). Imagine how big of a genome you would need to cover all possible viral substances by at least 1 innate gene! Read about hyper-mutation to understand the role of antibodies to detect even these highly evasive viruses.


Phagocytosis

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Phagocytosis, process by which certain living cells called phagocytes ingest or engulf other cells or particles. The phagocyte may be a free-living one-celled organism, such as an amoeba, or one of the body cells, such as a white blood cell. In some forms of animal life, such as amoebas and sponges, phagocytosis is a means of feeding. In higher animals phagocytosis is chiefly a defensive reaction against infection and invasion of the body by foreign substances (antigens).


Host vs. Pathogen

The Schistosoma worm has a parasitic relationship with humans. In this type of relationship, one organism, called the parasite, lives on or in another organism, called the host. The parasite always benefits from the relationship and the host is always harmed. The human host of the Schistosoma worm is clearly harmed by the parasite when it invades the host&rsquos tissues. The urinary tract or intestines may be infected, and signs and symptoms may include abdominal pain, diarrhea, bloody stool, or blood in the urine. Those who have been infected a long time may experience liver damage, kidney failure, infertility, or bladder cancer. In children, Schistosoma infection may cause poor growth and difficulty learning. Table (PageIndex<1>) lists some of the microscopic pathogens, their images, description, and the diseases that they cause.

Like the Schistosoma worm, many other organisms can make us sick if they manage to enter our body. Any such agent that can cause disease is called a pathogen. Most pathogens are microorganisms, although some, such as the Schistosoma worm, are much larger. In addition to worms, common types of pathogens of human hosts include bacteria, viruses, fungi, and single-celled organisms called protists. You can see examples of each of these types of pathogens in Table (PageIndex<1>). Fortunately for us, our immune system is able to keep most potential pathogens out of the body or to quickly destroy them if they do manage to get in. When you read this chapter, you&rsquoll learn how your immune system usually keeps you safe from harm &mdash including from scary creatures like the Schistosoma worm!


Complement proteins are inactive enzymes present in the plasma which are activated when they make direct contact with non-self-antigens. This starts a sequence of reactions that activates many complement proteins

  • Opsonisation: they coat the surface of a pathogen making it more susceptible to phagocytosis
  • Lysis: they can assemble into a membrane-attack complex which can actively damage the plasma membrane destroying the membrane integrity. Therefore, the cell loses osmotic pressure and water enters causing lysis
  • Immune Clearance: the removal of immune complexes from the circulation – cleans dead pathogens and antibodies

They also promote inflammation, attract macrophages and neutrophils through chemotaxis and cluster and bind pathogens together through agglutination


Molecular Biology of the Cell. 4th edition.

Our adaptive immune system saves us from certain death by infection. An infant born with a severely defective adaptive immune system will soon die unless extraordinary measures are taken to isolate it from a host of infectious agents, including bacteria, viruses, fungi, and parasites. Indeed, all multicellular organisms need to defend themselves against infection by such potentially harmful invaders, collectively called pathogens. Invertebrates use relatively simple defense strategies that rely chiefly on protective barriers, toxic molecules, and phagocytic cells that ingest and destroy invading microorganisms (microbes) and larger parasites (such as worms). Vertebrates, too, depend on such innate immune responses as a first line of defense (discussed in Chapter 25), but they can also mount much more sophisticated defenses, called adaptive immune responses. The innate responses call the adaptive immune responses into play, and both work together to eliminate the pathogens (Figure 24-1). Unlike innate immune responses, the adaptive responses are highly specific to the particular pathogen that induced them. They can also provide long-lasting protection. A person who recovers from measles, for example, is protected for life against measles by the adaptive immune system, although not against other common viruses, such as those that cause mumps or chickenpox. In this chapter, we focus mainly on adaptive immune responses, and, unless we indicate otherwise, the term immune responses refers to them. We discuss innate immune responses in detail in Chapter 25.

Figure 24-1

Innate and adaptive immune responses. Innate immune responses are activated directly by pathogens and defend all multicellular organisms against infection. In vertebrates, pathogens, together with the innate immune responses they activate, stimulate adaptive (more. )

The function of adaptive immune responses is to destroy invading pathogens and any toxic molecules they produce. Because these responses are destructive, it is crucial that they be made only in response to molecules that are foreign to the host and not to the molecules of the host itself. The ability to distinguish what is foreign from what is self in this way is a fundamental feature of the adaptive immune system. Occasionally, the system fails to make this distinction and reacts destructively against the host's own molecules. Such autoimmune diseases can be fatal.

Of course, many foreign molecules that enter the body are harmless, and it would be pointless and potentially dangerous to mount adaptive immune responses against them. Allergic conditions such as hayfever and asthma are examples of deleterious adaptive immune responses against apparently harmless foreign molecules. Such inappropriate responses are normally avoided because the innate immune system calls adaptive immune responses into play only when it recognizes molecules characteristic of invading pathogens called pathogen-associated immunostimulants (discussed in Chapter 25). Moreover, the innate immune system can distinguish between different classes of pathogens and recruit the most effective form of adaptive immune response to eliminate them.

Any substance capable of eliciting an adaptive immune response is referred to as an antigen (antibody generator). Most of what we know about such responses has come from studies in which an experimenter tricks the adaptive immune system of a laboratory animal (usually a mouse) into responding to a harmless foreign molecule, such as a foreign protein. The trick involves injecting the harmless molecule together with immunostimulants (usually microbial in origin) called adjuvants, which activate the innate immune system. This process is called immunization. If administered in this way, almost any macromolecule, as long as it is foreign to the recipient, can induce an adaptive immune response that is specific to the administered macromolecule. Remarkably, the adaptive immune system can distinguish between antigens that are very similar—such as between two proteins that differ in only a single amino acid, or between two optical isomers of the same molecule.

Adaptive immune responses are carried out by white blood cells called lymphocytes. There are two broad classes of such responses𠅊ntibody responses and cell-mediated immune responses, and they are carried out by different classes of lymphocytes, called B cells and T cells, respectively. In antibody responses, B cells are activated to secrete antibodies, which are proteins called immunoglobulins. The antibodies circulate in the bloodstream and permeate the other body fluids, where they bind specifically to the foreign antigen that stimulated their production (Figure 24-2). Binding of antibody inactivates viruses and microbial toxins (such as tetanus toxin or diphtheria toxin) by blocking their ability to bind to receptors on host cells. Antibody binding also marks invading pathogens for destruction, mainly by making it easier for phagocytic cells of the innate immune system to ingest them.

Figure 24-2

The two main classes of adaptive immune responses. Lymphocytes carry out both classes of responses. Here, the lymphocytes are responding to a viral infection. In one class of response, B cells secrete antibodies that neutralize the virus. In the other, (more. )

In cell-mediated immune responses, the second class of adaptive immune response, activated T cells react directly against a foreign antigen that is presented to them on the surface of a host cell. The T cell, for example, might kill a virus-infected host cell that has viral antigens on its surface, thereby eliminating the infected cell before the virus has had a chance to replicate (see Figure 24-2). In other cases, the T cell produces signal molecules that activate macrophages to destroy the invading microbes that they have phagocytosed.

We begin this chapter by discussing the general properties of lymphocytes. We then consider the functional and structural features of antibodies that enable them to recognize and neutralize extracellular microbes and the toxins they make. Next, we discuss how B cells can produce a virtually unlimited number of different antibody molecules. Finally, we consider the special features of T cells and the cell-mediated immune responses they are responsible for. Remarkably, T cells can detect microbes hiding inside host cells and either kill the infected cells or help other cells to eliminate the microbes.

  • Lymphocytes and the Cellular Basis of Adaptive Immunity
  • B Cells and Antibodies
  • The Generation of Antibody Diversity
  • T Cells and MHC Proteins
  • Helper T Cells and Lymphocyte Activation
  • References

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.


Module 7 / Inquiry Question 2

In this week, we will have a look at the responses of plants and animals that are used to protect themselves against pathogens & infection as per Inquiry Question.

For plants, we will be focusing on virus and fungi pathogens. Specifically, there will be exploration into plants’ first and second line of defence.

In the case of animals, we will be using humans as an example and be looking into the three lines of defence that makes up our immune system.

Without further ado, let’s start munching on the delicious knowledge!

Learning Objective #1 - Investigate the response of a named Australian plant to a named pathogen through practical and/or secondary-sourced investigation, for example:

- Fungal pathogens- Viral pathogens

Plants have both innate and induced disease resistance mechanisms.

The former is the plants’ first line of defence and the latter can be termed the plants’ second line of defence.

The plant’s innate disease resistance responses involves the:

Cell wall & cuticle preventing water loss and act as a physical barrier to prevent pathogens enter leaf.

NOTE: Varying properties of cell wall and cuticle can be acquired via adaptation.

Antimicrobial chemicals such as nicotine which naturally occurs in some plants.

Naturally occurring enzyme inhibitors.

The cell’s second line of defence involves both general (non-specific) and specific immunity.

In general-induced immunity, it involves pattern recognition receptors that are present on plants’ cell wall which are able to recognise microbe-associated molecule patterns.

When these microbial patterns are identified by the receptors, various responses are triggered via signalling pathways resulting in:

Production of lignin to reinforce cell wall. Lignin produced also allows the modification of cell wall structure by blocking the plasmodesmata (the channel allowing molecules to through the cell wall) is blocked, thus hindering the flow of pathogen from one cell to another.

Production and accumulation of proteins into the cell membrane such as chitinase, glucanase and protease. These proteins are able to inhibit effectors that are secreted by pathogens and stop reproduction & growth of pathogen. We will examine what effector molecules are and what they do soon.

Production & secretion of antimicrobial molecules such as nitric oxide (NO) or hydrogen peroxide (H2O2).

Production & secretion of signalling hormones such as salicylic acid and jasmonic acid.

Activation of genes to produce more antimicrobial enzymes and proteins (e.g. chitinase, glucanase and protease as mentioned earlier) to stop the reproduction & growth of pathogens.

It is important to note that pathogens have adapted to avoid the detection or recognition of microbe-associated molecule patterns which can led to the plant’s general-induced defence mechanism not being triggered. These pathogens can secrete effector molecules.

Effectors are molecules secreted by pathogens to suppress the plant’s general-induced defence mechanisms, allowing the pathogen to invade and obtain nutrients from plant cells.

In the specific – induced immunity in plants, the hypersensitive response is involved.

This only occurs when the plant identified and recognises a specific antigen.

NOTE: An antigen is a protein molecule present on the pathogen (or they can be proteins secreted by the pathogen).

There are resistance proteins that are present in the plants’ cell membrane situated near (or guarding) the proteins. These resistance proteins are also found inside plant cells.

The specific-induced immunity response involves resistance proteins recognising the antigen which triggers responses via a signalling pathway. These signals produced as a result of the recognition of pathogen’s effectors by resistance proteins result in the activation of genes in plant that are responsible for the coding and production of enzymes, antimicrobial (e.g. phytoalexins) and oxidative molecules to hydrolyse proteins, nuclear membrane and nucleic acid which breaks them down. This would results in apoptosis.

Apoptosis is essentially programmed death of infected cells and surrounding cells of infected cell so stop the spread of pathogens, effector molecules and infection in general.

NOTE: This response is the last defence barrier to defend against pathogen and their effectors that have invaded the cytoplasm and vascular systems.

Response of Potato Plant to Fungi

Host: Ipomoea costata (Potato Plant).

Pathogen: Phytophthora Infestans (Fungi).

Disease: Late Blight (or Potato Blight).

The potato plant’s example is same as the general-induced immunity and specific-induced immunity as we have examined in the above section.

So, you can write them and replace the word ‘pathogen’ with the word ‘Fungi’ in your written response in exams.

However, we will go over some points that are specific to the late blight disease:

We mentioned about microbe-associated molecule patterns detected by pattern recognition receptors in the previous section. Well, the specific response of potato plant is that their pattern recognition receptors can recognise beta-glucans that is present on the phytophthora infestans’ (fungi) cell wall. Here, beta-glucan is a type of microbe-associated molecule pattern.

NOTE: There are many more of these microbe-associated molecule patterns that plants may recognise but we, humans, have not yet discovered.

When the pattern recognition receptor recognises the microbial pattern (i.e. beta glucans), the protease protein is produced as a response to inhibit the effectors molecules produced by the fungi’s hyphae and stop the growth of the pathogen. This therefore stop the pathogen’s (or the hyphae) invasion to obtain nutrients from the plant’s cells that are necessary for fungi growth & survival.

NOTE: When asked about plants’ response to VIRUS PATHOGENS, you can use the same notes about general-induced and specific-induced immunity response as explored previous section.

To answer your question, yes, virus also produces effector molecules and plants response to them in the same way, at least at HSC Biology level.

You will learn at university that the type of effector molecules, microbe-associated molecule patterns will differ for fungi and virus due to the pathogen’s difference in chemical composition. However, it’s not necessary to explore such differences at HSC Biology level.

We will provide you a named example of virus affecting a plant that you can use in your exams

Host: Tomato Plant

Pathogen:Tomato Spotted Wilt Virus

Disease: Tomato Spotted Wilt

NOTE: If you have another example, you can use that too. It doesn’t really matter.

Learning Objective #2 - Analyse responses to the presence of pathogens by assessing the physical and chemical changes that occur in host animal cells and tissues.

First Line of Defence (Innate Immune Response)

Antigens are molecules (usually proteins) which the host recognise as being foreign and initiate the adaptive immune response (e.g. the production of antibodies to destroy the antigens) and innate immune response (e.g. phagocytosis).

We will explore both the components of innate and adaptive immune response in detail this week’s notes.

There are two types of antigens being exogenous and endogenous.

Exogenous antigens are basically found on the invading pathogen itself.

Endogenous antigens are found in the (harmful and/or toxic) chemicals that are produced by the pathogen when it has entered the host organism.

Lit! Now that we have covered the basis of antigens which will become useful when we explore the second and third line of defence, we can start exploring the first line of defence.

The first line of defence involves the physical and chemical barriers that helps to stop further entry, growth and reproduction of invading pathogens.

The physical barriers constituting to the first line of defence in animals (such as humans) include:

Mucous Membranes

The chemical barriers that makes up the first line of defence are:

Acidic conditions in stomach

Alkaline conditions in intestines

Body secretions – urine, lysozymes, saliva.

NOTE: The first line of defence is non-specific to the invading pathogen. That is, it does not operate differently based on the type of pathogen that is present.

Skin

The skin is a large physical barrier (and an organ) that protects cells from pathogens in the surrounding environment.

Since the surface of the skin is waterproof, it is able to be maintained at a dry state which hinders the growth of pathogens.

Sweat glands are also able to produce sweat which naturally occurring bacteria on our skin can breakdown to produce acidic chemicals. This creates an acidic environment that also hinders the growth of pathogens.

NOTE: The skin is a very noice physical barrier <O

Yes, if you experience a cut, your blood will clot due to the presence of platelets in your blood. This will temporary shield your deeper tissues from being exposed to microbes in the environment. However, that’s not an excuse to not maintain noice, smooth, healthy skin.

Mucous Membranes

The mucous membranes are on the surface of the respiratory, digestive, reproductive and urinary tracts. As the name suggests, they produce thick mucus which is able to trap pathogens and antigens.

Saliva that travel across these membranes contain enzymes such as lysozymes that is able to breakdown pathogens.

The moist and nutrient-rich environment of the mucus membranes are able to support the growth of natural, beneficial microbes that produces chemicals capable of hindering the growth and entrance of pathogen.

Cilia

These are tiny-like structures that are located along the respiratory tract.

They vibrate or move at upright direction, resulting mucus (containing trapped pathogens) being propelled to the throat which can be coughed or sneezed out.

Acidic & Alkaline Environments

Our stomach contains hydrochloric acid which is very acidic .

This high level of acidic is able to dissolve pathogens or mucus that contains any trapped pathogens.

Similarly, the alkaline environment in our intestines are able to decompose and kill pathogens.

Body Secretions - Urine, Lysozymes and Saliva

Urine that produced from the kidney passes through the walls of the ureter and bladder. As urine is acidic, this washing of the walls of the ureter and bladder helps kill and hinder the growth of microbes (e.g. pathogens).

Saliva in our mouth are contains enzymes called lysozymes that is capable of decomposing their protective cell wall of bacteria which led to their eventual decomposition. This therefore prevents infection from the pathogen. Tears also contain lysozymes that allow us to flush off any pathogens on the surface of our eye (cornea).

We will explore more about the eye soon in Module 8!

Second Line of Defence (Innate Immune Response)

Moving onto the second line of defence!

For humans, the second line of defence deal only physiological adaptations of the organism.

The physiological defence adaptations that makes up the second line of defence include:

Phagocytosis

Lymphatic System

Inflammation Response

Cell death to seal off pathogens & Antigens

Interferons & complement proteins

NOTE: Similar to the first line of defence, the second line of defence is also non-specific to to the invading pathogen.

Let’s explore each of the physiological adaptations that makes up the second line of defence in our body.

Phagocytosis

Phagocytes are a type of leucocytes (i.e. specialised white blood cells) that is responsible for phagocytosis.

There are two types of phagocytes, these being neutrophils and macrophages.

Phagocytosis can be defined as the defence mechanism whereby phagocytes modify to their shape to envelope or enclose a non-specific antigen (e.g. a pathogen).

The advantage of phagocytes is that it is able to distinguish self markers and non-self (not belonging to the host) markers.

Therefore, phagocytes will only operate or engulf matter that are foreign to the body.

When the phagocyte has ‘engulfed’ the antigen, it will combine with a lysosome, which contains digestive enzymes (e.g. protease) produced by Golgi Apparatus, to breakdown the microbe or antigen.

Following this, the decomposed matter derived from the antigen is let out by the phagocyte. As the chemical structure of the antigen has been largely altered due to the action of enzymes in lysosome, the decomposed matter of antigen is not toxic or harmful to the host’s cells.

Phagocytosis is useful because when the antigen is engulfed by the phagocyte (e.g. macrophage), any of the toxins that it secretes will be contained in the macrophage and not be secreted to harm other cells. Also any reproduction will occur inside the macrophage will be destroyed by lysosomes’ enzymes upon combination.

Another benefit of phagocytosis (and other mechanisms in the 2nd line of defence that we will explore soon) is that minimises the reproduction of the pathogen & harmful effects caused by pathogen before the adaptive immune response (3rd line of defence) is initiated.

You will see later that the third line of defence involves B and T cells involved in initiating the adaptive immune response need to bind with a specific antigen. This binding process is not immediately and so the 2nd line of defence is good at minimising the quantity and damage caused by invading pathogen before the adaptive immune response hopefully ‘saves the day’.

NOTE: In some scenarios, the antigen may avoid being engulfed and phagocytosis is unsuccessful.

Phagocytes assist the 3rd line of defence as the phagocyte that engulfed the antigen will move & display some of the antigen on its surface. The phagocyte can then present this antigen to cells (lymphocytes) that make up the 3rd line of defence and activate lymphocytes.

Lymphatic System (Lymph System)

The role of the lymph system is to filter and return intercellular fluid to the blood using lymph nodes connected by lymph vessels.

The lymphatic system therefore is comprised of lymph vessels that joins lymph nodes together.

NOTE: The fluid that flows through the lymph vessels is known ‘lymph’.

The lymph nodes in the lymphatic system has the ability to filter and trap antigens. It is within the lymph nodes where B and T lymphocytes are stored.

NOTE: Lymphocytes is a type of specialised white blood cell (e.g. leucocyte).

We will explore more about lymphocytes when we examine the third line of defence.

So, essentially, the lymph nodes in the lymph system facilitate the lymphocytes to bind with antigen and initiate an adaptive immune response.

It is important to note that the interaction of lymphocytes with antigens is NOT a second line of defence mechanism, rather it is 3rd line.

We are ONLY dealing with filtering and trapping antigens when we are talking about the lymph system.

Inflammation Response

Alright, now we have arrived to explore the inflammation response as a defence mechanism in the second line of defence.

Again, like all other defence mechanisms that makes up to the second line of defence, the inflammation response is non-specific to an antigen or a pathogen.

The inflammation response is initiated by infected cells releasing chemicals known as histamines and prostaglandins. These chemicals act on blood vessels causing vasodilation (e.g. dilation of blood vessel), resulting in higher level of blood flow through the site of infection.

Remember that our blood contains red blood cells which are red in colour. Due to vasodilation, a higher blood flow would mean that there are more red blood cells at the site of infection. As a result of this, the site of infection appears to be red and swollen (and hot).

So, inflammation responses occur at sites of infection.

As our blood is hot, this increased blood flow to the site of infection would increase the temperature of the environment surrounding the infected cells at the infected site.

Due to this increase in temperature, it slows the rate at which pathogens reproduce their enzymes and protein such as effector molecules that are required for the pathogen’s invasion, survival and successful reproduction.

On top of dilating the blood vessels, histamine also increases the permeability of capillaries which allows more white blood cells to move to the infected cells. These white blood cells include macrophages which can engulf antigens (e.g. toxins produced by pathogen) or pathogens themselves at the site of infection.

Cell death to seal off pathogens & Antigens

When the infected cell(s) is not suppressed from transmitting disease, the second line of defence have the mechanism involving neighbouring cells dying to form a wall of dead cells surrounding infected cell(s), forming a capsule structure known as granuloma.

The granuloma has a three-layer structure.

The first layer involves different types of phagocytes surrounding the infected cells.

The next outer layer is comprised of lymphocytes surrounding the phagocytes.

The final layer is made up of fibre cells to consolidate and envelope the structure.

Since the pathogens are deprived from food supply by being contained in the granuloma, it will die. The death of antigens & pathogen prevents the transmission of the disease to healthy cells.

Interferons & Complement Proteins

When cells are infected by a virus, they are able to secrete proteins called interferons.

The effect of interferons is that they induce neighbouring unaffected cells to produce antiviral chemicals which help reduce protein synthesis activity. This means that the amount of viral particles that are reproduced is reduced. This limits the transmission of disease between cells.

If the neighbouring cells are infected with the virus, it would signal the infected cells to perform apoptosis.

Complement proteins are produced by liver cells and makes up the complement system comprised of a collection of 20 types proteins that circulate the blood.

These proteins stimulate phagocytes activity to allow more phagocytes to travel towards site of infection. We will discuss more about how these proteins when we discuss about antibodies soon.

Third Line of Defence (Immune Response)

NOTE: The ‘adaptive immune response’ refers to the third line of defence.

The term ‘adaptive immunity’ refers to the host cells’ ability to recognise and defend against invading antigens.

NOTE: This section will be covering next week’s notes which is about the adaptive immune response (third line of defence).

The adaptive immune response in humans involves three different biological molecules, these being:

They play a role in the third line of defence in humans and have interactions with each other which we will explore now.

T - Lymphocytes

As we have mentioned earlier, lymphocytes are a type of specialised white blood cells (i.e. leucocyte).

In the case of T lymphocytes, they are manufactured in the bone marrow and mature in thymus gland (located near your lungs).

Upon maturation, the cells are released into the bloodstream whereby it is transported into the lymph vessel and stored in the lymph nodes.

T cells are also stored in lymphatic tissues in the spleen, thymus, tonsils and liver.

T lymphocytes have a surface receptor protein that can recognise a specific antigen. For instance, often after phagocytosis, some parts of the pathogen or antigen is re-located or moved to the surface of the phagocyte
(e.g. macrophage). These phagocytes will move into the lymph (fluid) whereby they will encounter lymphocytes stored in the lymph node.

The lymphocyte may have surface receptor proteins that matches with the protruding antigen which the phagocyte engulfed.

If we assume that the lymphocyte’s surface receptor proteins matches the antigen, the T lymphocyte will then be activated.

There are many types of T lymphocytes, these include:

Cytotoxic T cells (also known as Killer T cells).

It is Helper T cell that activates other types of T cells via cytokines, so usually we start with T helper cells when examining the interaction between T cells and antigens.

NOTE: You should always be specific in your response when talking about T cells. That is, you should not say that ‘T cells are activated’. Rather, you should say the specific name of the T cell that you are talking about, for example, ‘Helper T cells are activated’ or ‘Cytotoxic T cells are activated’.

Anyways, let’s get back on the topic of activated Helper T cells after its surface receptor protein matches and binds with the antigen.

When Helper T cells are activated, it will clone and differentiate sub-types of Helper T cells that differ in the cytokines that they produce. These cytokines that Helper T cells produce will help clone and activate other specific T cells such as cytotoxic T cells, memory T cells and suppressor T cells.

These different types of T cells that are produced all have the SAME specific receptor protein that is present in the original Helper T cell which they are derived from.

Hence, the different types of T cells produced are specific to the same antigen which the original Helper T cell was activated by.

The cytotoxic T cells that are produced will travel towards infected cells and release cytotoxins to eliminate the infected cells which thereby destroys the antigen(s).

The activated helper T cells will also secrete cytokine molecules that activates B lymphocytes, causing them to divide and differentiate into plasma cells and memory B cells.

NOTE: Plasma cells will produce antibodies as we will learn later.

Moreover, cytokine molecules have the function to increase the rate at which macrophages is able to phagocytose antigens as well as enhancing the inflammation response (2nd line of defence).

Lastly, the increase in cytotoxic T cells being produced (from Helper T cell activation) is also caused by cytokines.

When all the antigen has been destroyed, suppressor T cells are responsible to bind with matching antigen with its surface receptor protein in order to suppress B lymphocytes and cytotoxic T cells and other T cells that recognises the same antigen.

So, in essence, suppressor T cells regulate the adaptive immune response.

We will now explore the role of B lymphocytes in the human’s adaptive immune response.

B - Lymphocytes

Like T lymphocytes, B lymphocytes are also a type of specialised white blood cells (leucocyte).

They are manufactured in the bone marrow and also mature there. In the case of T-cells, we mentioned that they are produced in the bone marrow but mature in the thymus gland.

After maturation, the B cells will move form the bone marrow to lymph nodes and lymphatic tissues via blood.

Again, similar to T cells, B lymphocytes also have a specific surface antibody protein that can recognise and is specific to a particular antigen.

Suppose that we have B lymphocyte’s surface antibody successfully binding with an antigen. If this occurs, the B cell, bounded to the antigen, will travel and present the antigen to a Helper T cell. The Helper T cell, which the B cell presents antigen to, will also have a surface receptor protein that is specific to (i.e. matches) the antigen.

If the Helper T cell, which the B cell presented the antigen to, has matching surface receptor protein to the antigen, it will become activated.

Upon activation, the helper T cell will perform the activities that we have mentioned previously. For instance:

They will secrete cytokines to activate more Helper T cells with the same surface receptor protein that’s specific to the antigen.

The cytokines that Helper T cells produce will help clone and activate other T cells – e.g. cytotoxic, memory T cells, suppressor T cells, etc.

Etc … Please review the previous section about ‘T Lymphocytes’ to review on all other activities.

Now, we did mention in the previous section when we examined T Lymphocytes where we said that activated Helper T cells will secrete cytokine molecules that will stimulate or activate B lymphocytes that has surface antibody that is matching the antigen that caused the Helper T cell to be activated.

As a result of the B cell being activated due to cytokine (i.e. interleukin-2), it will divide and differentiate into plasma cells and memory B cells. Again, these plasma and memory B cells also have surface antibody proteins that are specific to the antigen which the Helper T cell was activated by.

These plasma cells is responsible for producing antibodies that has a surface receptor protein that capable of binding to the antigen that was activated the Helper T cell that ultimately gave rose to the the antibodies via B cell activation.

These antibodies that are produced by the plasma cells are secrete into the lymph and blood to bind with an antigen.

An antigen-antibody complex is formed when the antibody produced by the plasma cell binds to a matching antigen. Upon successful binding, the pathogen or antigen is inhibited from being harmful other cells.

We will examine several ways the antibody can inhibit the harmful activities of pathogen in the next section.

Phagocytosis can then be performed on the antigen-antibody complex whereby a phagocyte can enclose or engulf the complex. The antigen is digested upon combination of phagocyte with lysosome whereby the lysosome secretes lysozymes as we have mentioned earlier in the second line of defence.

Now, you may ask what Memory B cells does?

Memory B cells will remain in the lymph nodes and lymphatic tissues and have similar properties to B cells. That is, they also have surface antibodies that can recognise a specific antigen.

When memory B cells are activated by the same antigen (e.g. individual’s re-exposure to same pathogen few years later), the memory B cell will undergo mitosis and differentiate into plasma cells in about 4 days where the plasma cells will then produce antibodies. Due to memory B cells, a secondary exposure to the same antigen means that the individual will not experience the symptoms!

Memory B cells also undergo somatic hypermutation which results more antibodies are produced in the secondary exposure to the same antigen (secondary immune response) than during primary immune response (i.e. when individual gets exposed to the antigen for the first time).

Memory B cells are also more abundant than B cells. This along with the fact that memory B cells have higher affinity surface receptor proteins than B cells after memory B undergoing somatic hypermutation, it allows memory B cells to be more quickly activated than B cells.

Memory T Cells

Recall that we also mentioned about memory T cells earlier. When the host organism is exposed to the same antigen again (perhaps could to due to exposure to the same pathogen), these memory T cells will have the same surface receptor protein that activated the Helper T cells the first time that produced the memory T cells.

The memory T cells with matching surface receptor protein to the antibody will clone and differentiate into other T cells such as cytotoxic T cells and Helper T cells. We have already talked about the role of these T cells earlier.

NOTE: There are more memory T cells than Helper T cells which is why the secondary exposure to the same pathogen (with same antigen) is quicker than when the individually exposed to the pathogen for the first time. It also easier to activate, thus taking less time, for memory T cells to differentiate into other T cells (e.g. cytotoxic cells) compared to Helper T cells.

Due to memory T cells, a secondary exposure to the same antigen means that the individual will notexperience the symptoms!

Antibodies

Lastly, we have antibodies which we have already discussed in the above ‘B lymphocytes’ section.

In summary, antibodies are also called immunoglobulins which are proteins produced by plasma cells.

Antibodies are Y-shaped, each with two antigen binding sites.

We mentioned earlier that plasma cells are produced via the activation of B cells or Memory B cells and the produced antibodies will have antigen binding sites that matches the antigen that activated the B cells and Memory B.

Upon successful binding, antibody is able to immobilise the antigen or block their receptors that are used in host cell entry.

Antigen-antigen complex provides a site for complement proteins to bind to which is able to attract phagocytes to bind to them and destroy the antigen.

NOTE: We have talked about the nature of complement proteins in the 2nd line of defence.

Basic Flowchart To Summarise Adaptive Immunity

(3RD LINE OF DEFENCE)

Remember that there are many ways which Helper T cells can be activated by antigen.

For example, as we have already mentioned in the T Lymphocytes section, phagocytes can present some fragments of its engulfed antigen on their surface and move to present the antigen to activate Helper T cells.


Why Don’t Antibodies Guarantee Immunity?

Photo by Jandro Saayman.

Editor’s Note: This is a guest post by Greer Arthur, a specialist in the global health program in NC State’s College of Veterinary Medicine (CVM). Special thanks to Susan Tonkonogy, CVM associate professor of immunology, for reviewing this interview.

With millions of COVID-19 cases reported across the globe, people are turning to antibody tests to find out whether they have been exposed to the coronavirus that causes the disease. But what are antibodies? Why are they important? If we have them, are we immune to COVID-19? And if not, why not?

These are important questions. Antibody tests can detect the presence of antibodies in the blood that bind to the coronavirus that causes COVID-19. You may have heard news reports explaining that antibody tests are key to slowing the infection rate. You may also have heard medical experts warn that having the antibodies may not guarantee immunity against a second COVID-19 infection. To help you get a handle on what these health experts are talking about, we spoke to Jonathan Fogle, associate professor of microbiology and immunology in the CVM at NC State.

The Abstract: What are antibodies, and how do we make them?

Jonathan Fogle: Antibodies, also known as immunoglobulins (Ig), are specialized proteins that bind to a uniquely shaped object – called an antigen – that is found on the surface of a pathogen. These pathogens can be things such as bacteria or viruses. Antibodies are produced by B lymphocytes, known as B cells, which are specialized white blood cells of the immune system. B cells have antibodies on their cell surface that allow them to recognize anything foreign. When they encounter a pathogen, the B cells transform into plasma cells, which start producing antibodies that are designed to bind to an antigen that is specific to this pathogen.

TA: How do antibodies stop an infection?

Fogle: Plasma cells release large amounts of antibody into the body’s circulation. This protects us in two main ways. First, antibodies can bind to antigens on the outside of the pathogen to stop it from entering our cells. This is particularly important for viruses, which enter human cells to replicate (so if the virus is stopped from entering your cells, you won’t get sick). Second, by binding to antigens on the pathogen, antibodies also signal other white blood cells known as phagocytic cells, which engulf and destroy the pathogen. So, in short, antibodies can both neutralize a virus and mark it for destruction.

Antibodies protect us by binding to pathogens, which both prevents the pathogens from entering our cells and labels the pathogens for destruction by phagocytes.

TA: Why do we produce antibodies?

Fogle: Antibodies form part of our adaptive immune response, which is a refined, targeted response to a specific antigen. The first time we encounter a virus, some of our B cells become plasma cells, but others transform into memory B cells. The second time you’re exposed to the same pathogen, these memory cells quickly transform into plasma cells that produce large amounts of antigen-specific antibodies to fight the infection.

The first time someone is infected by a specific pathogen, it normally takes a few weeks to manufacture antigen-specific antibodies. But if we are re-exposed to the same pathogen, the production of antigen-specific antibodies is rapid, usually within the first day. This is why we’re so dependent on vaccines to protect us from a lot of pathogens. Vaccines usually contain pieces of the pathogen that can stimulate our immune systems to manufacture antigen-specific antibodies and produce memory cells. So if we are exposed to this pathogen again, we are already prepared to respond very quickly.

TA: If we have antibodies, does this mean we will always be protected?

Fogle: This novel coronavirus is new to the human population – we have never been exposed to it before – so there are many unknowns about how we respond to it. Across any population, there is a high degree of individual variability in our antibody responses to a pathogen in the amount, type and quality of antibodies that we make.

Some people make many high quality antibodies that are very good at recognizing the relevant antigen and binding to it. If this happens, the virus is rapidly bound by antibodies and eliminated before it can even cause an infection.

Other people make antibodies, but they’re not as effective at binding the pathogen. In this situation, the antibodies only provide partial protection: they slow the virus down but the virus can still cause some degree of infection. These individuals usually exhibit some symptoms and shed the virus for a longer period of time.

There are also some people who either produce very little or very poor quality antibodies. In this case, although these people produce antibodies, the immunity is not very effective so they can experience prolonged infection with more severe symptoms. They are also likely to be re-infected at a later point in time. This is one of the big unknowns with this new coronavirus: What percentage of the population falls into this category?

TA: Do antibodies always form after an infection?

Fogle: We generally expect antibodies to form following infection, but there are certain cases where this might not occur.

The adaptive immune system, which is what we have been talking about so far, is only one part of our immune response. We also have another type of immune system known as the innate immune system. The innate immune system is our frontline defense, the first system to respond to a new infection. This includes cells such as neutrophils, macrophages and dendritic cells. Unlike the adaptive immune system, which includes antigen-specific antibodies that take time to develop, the innate immune system responds to antigens very quickly but in a non-specific way. It attacks anything that “looks” foreign to the body, like components of a bacterial cell wall, or viral RNA and DNA. Quite often, the innate immune response will take care of an infection before the adaptive immune system even has a chance to start manufacturing antibodies.

The adaptive immune system involves more than just B cells, plasma cells and antibodies – it also includes T cells. T cells are another population of white blood cells that can develop into memory cells, just as B cells can. They can also differentiate into specialized cells that kill virus-infected cells. The functions of T cells and B cells are different. B cells develop into plasma cells that produce antibodies (T cells do not) T cells directly kill virus-infected cells (B cells do not). Sometimes individuals with a very vigorous T cell immune response will be protected from a pathogen even though they produce low amounts of antibody. The T cell immune response is much more difficult to measure than the antibody response and is usually only evaluated in specialized research settings.

T cells are not antibodies – but they are important. T cells are another type of white blood cell that work alongside B cells to fight infections. The “T” stands for thymus, which is where the cells develop.

TA: Why do we need an adaptive immune response?

Fogle: Our adaptive immune response is important because once developed, it is highly specific for the pathogen and provides us with immunologic memory. This serves two purposes.

First, it helps build herd immunity. If enough people in a population have immunologic memory, the second wave of infection typically occurs in smaller clusters instead of spreading like wildfire and overwhelming the population (and thus our hospitals). This is why social distancing is so important right now – it’s limiting the spread of disease and helping to ensure that our hospitals are not overwhelmed.

Secondly, our adaptive immune system protects us as we age. Our immunologic memory can last for a very long time. People in their 80s or 90s still maintain immunologic memory to pathogens and vaccines that they were exposed to as children, such as influenza or the measles vaccine.

Our capacity to generate immunologic memory is greatest from childhood into late adolescence because the bone marrow, where B cells mature, and the thymus, where T cells mature, are most efficient and productive at younger ages. As we advance into adulthood, these production systems decline and we gradually lose our ability to generate a vigorous adaptive immune response to new pathogens, particularly in later stages of life.

This is what we’re really worried about with this COVID-19 virus. In general, our elderly population has effective immunologic memory to things that they were exposed to when they were younger, but because this is a new virus, elderly people might have a difficult time generating an adaptive antiviral immune response. This is often compounded by other underlying diseases that weaken the adaptive immune responses.

Our adaptive immune response generates immunologic memory, which can protect us from pathogens throughout our lifetimes. However, our ability to form adaptive immune responses against new pathogens declines as we age.

TA: Does this mean we can’t generate new antibodies against new infections when we’re older?

Fogle: Not exactly. As we get older, the immune response isn’t absent, it’s just diminished. By the time you’re in your 80s or 90s, you’re less efficient at generating immunity to newly encountered pathogens than during childhood or as a young adult. The adaptive immune response also exhibits a high degree of variability between individuals. Some people in their 80s and 90s still have an excellent adaptive immune response to new things, but many do not.

TA: Why can’t we rely entirely on our innate immune response when we lose our ability to generate an adaptive immune response?

Fogle: This is one of the big unknowns with COVID-19. In general, we think the innate immune response remains fairly intact throughout life, even in elderly individuals. The problem is, if we have a very poor adaptive immune response, our innate immune response has to overcompensate to make up for it. This is known as immune dysregulation and may be one of the reasons we observe more severe infections in older patients.

TA: Is this related to why some coexisting conditions worsen the effects of an infection?

Fogle: We know that, in general, chronic diseases tend to suppress our immune systems because different parts of our body are not functioning efficiently and together. The immune system is a complex network of lymph nodes, the spleen, bone marrow and other organs. The system needs a proper functioning environment to generate an effective response. This is why people with underlying chronic disease often have some loss of innate and adaptive immunity and therefore are at greater risk for developing a more severe infection.

TA: Not all antibodies last forever. Why does immunologic memory sometimes fade?

Fogle: We still don’t know how, why and for how long immunologic memory lasts for every infectious disease. Immunologic memory is probably one of the most complicated things we study in immunology. What we do know for most pathogens and vaccines is that, especially from childhood to adolescence, if we are exposed to something multiple times, we generate robust and long-term immunity.

But as we age, although we may develop some adaptive immunity, the memory doesn’t seem to last as long. This probably has to do with the age at which we’re exposed to the pathogen and how good the pathogen is at inducing immunity. It is also linked to how many times we are exposed to or vaccinated against a pathogen. We generally generate our maximal number of memory cells with three to five exposures, meaning that being exposed more than three to five times will not further increase the overall number of memory cells.

TA: Why is it important to understand more about COVID-19 antibodies?

Fogle: Antibodies can tell us who has been exposed to a pathogen and potentially what protection they might have against a re-infection. As we discussed above, there are many unknowns with this new coronavirus. We need to know more about how we as individuals and a population are responding to the virus, particularly whether immunity to the virus is mediated by antibodies, T cells or both. Armed with this information, we will be better able to design safe and effective vaccines and to predict outcomes for individuals who become infected.


Some pathogens reproduce by infecting body cells. With neutralization, antibodies bind with the pathogen and form antibody/pathogen complexes. These complexes incapacitate the pathogen by preventing it from communicating with other cells in the body. If the pathogen cannot communicate, it dies off. Imagine a computer system with a sophisticated firewall. The firewall detects an intrusion and closes the port before the virus or Trojan horse can invade the computer and communicate with the other files.

The immune system has specialized white blood cells called phagocytes. These cells are designed specifically to destroy and consume enemy cells. With opsonization, antibodies bind to the pathogen and release a chemical to attract the phagocytic cells. Imagine a guard dog (antibodies) cornering a burglar and barking to signal his location until someone arrives to take the burglar to jail.


Examples of Phagocytosis

Phagocytes are found throughout the human body as white blood cells in the blood. One liter of blood contains approximately six billion of them! Many different types of white blood cells are phagocytes, including macrophages, neutrophils, dendritic cells, and mast cells. White blood cells are known as “professional” phagocytes because their role in the body is to find and engulf invading bacteria. “Non-professional” phagocytes include other types of cells like epithelial cells, endothelial cells, and fibroblasts. These cells sometimes perform phagocytosis, but it is not their primary function.

As mentioned earlier in the article, amoebae perform phagocytosis in order to consume food particles. Amoebae engulf particles by surrounding them with pseudopods, which are temporary armlike projections of the cell that are filled with cytoplasm. Ciliates are another type of organisms that use phagocytosis to eat. Ciliates are protozoans that are found in water, and they eat bacteria and algae. Both amoebae and ciliates are protists, organisms that have eukaryotic cells but are not animals, plants, or fungi.


Contents

The Russian zoologist Ilya Ilyich Mechnikov (1845–1916) first recognized that specialized cells were involved in defense against microbial infections. [16] In 1882, he studied motile (freely moving) cells in the larvae of starfishes, believing they were important to the animals' immune defenses. To test his idea, he inserted small thorns from a tangerine tree into the larvae. After a few hours he noticed that the motile cells had surrounded the thorns. [16] Mechnikov traveled to Vienna and shared his ideas with Carl Friedrich Claus who suggested the name "phagocyte" (from the Greek words phagein, meaning "to eat or devour", and kutos, meaning "hollow vessel" [1] ) for the cells that Mechnikov had observed. [17]

A year later, Mechnikov studied a fresh water crustacean called Daphnia, a tiny transparent animal that can be examined directly under a microscope. He discovered that fungal spores that attacked the animal were destroyed by phagocytes. He went on to extend his observations to the white blood cells of mammals and discovered that the bacterium Bacillus anthracis could be engulfed and killed by phagocytes, a process that he called phagocytosis. [18] Mechnikov proposed that phagocytes were a primary defense against invading organisms. [16]

In 1903, Almroth Wright discovered that phagocytosis was reinforced by specific antibodies that he called opsonins, from the Greek opson, "a dressing or relish". [19] Mechnikov was awarded (jointly with Paul Ehrlich) the 1908 Nobel Prize in Physiology or Medicine for his work on phagocytes and phagocytosis. [7]

Although the importance of these discoveries slowly gained acceptance during the early twentieth century, the intricate relationships between phagocytes and all the other components of the immune system were not known until the 1980s. [20]

Phagocytosis is the process of taking in particles such as bacteria, parasites, dead host cells, and cellular and foreign debris by a cell. [21] It involves a chain of molecular processes. [22] Phagocytosis occurs after the foreign body, a bacterial cell, for example, has bound to molecules called "receptors" that are on the surface of the phagocyte. The phagocyte then stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes. [23] Once inside this phagocyte, the bacterium is trapped in a compartment called a phagosome. Within one minute the phagosome merges with either a lysosome or a granule to form a phagolysosome. The bacterium is then subjected to an overwhelming array of killing mechanisms [24] and is dead a few minutes later. [23] Dendritic cells and macrophages are not so fast, and phagocytosis can take many hours in these cells. Macrophages are slow and untidy eaters they engulf huge quantities of material and frequently release some undigested back into the tissues. This debris serves as a signal to recruit more phagocytes from the blood. [25] Phagocytes have voracious appetites scientists have even fed macrophages with iron filings and then used a small magnet to separate them from other cells. [26]

A phagocyte has many types of receptors on its surface that are used to bind material. [2] They include opsonin receptors, scavenger receptors, and Toll-like receptors. Opsonin receptors increase the phagocytosis of bacteria that have been coated with immunoglobulin G (IgG) antibodies or with complement. "Complement" is the name given to a complex series of protein molecules found in the blood that destroy cells or mark them for destruction. [27] Scavenger receptors bind to a large range of molecules on the surface of bacterial cells, and Toll-like receptors—so called because of their similarity to well-studied receptors in fruit flies that are encoded by the Toll gene—bind to more specific molecules. Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to release a group of hormones that cause inflammation. [2]

The killing of microbes is a critical function of phagocytes that is performed either within the phagocyte (intracellular killing) or outside of the phagocyte (extracellular killing). [28]

Oxygen-dependent intracellular Edit

When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called a respiratory burst, produces reactive oxygen-containing molecules that are anti-microbial. [29] The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in compartments inside the cell. This method of killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types. [14]

The first type is the oxygen-dependent production of a superoxide, [2] which is an oxygen-rich bacteria-killing substance. [30] The superoxide is converted to hydrogen peroxide and singlet oxygen by an enzyme called superoxide dismutase. Superoxides also react with the hydrogen peroxide to produce hydroxyl radicals, which assist in killing the invading microbe. [2]

The second type involves the use of the enzyme myeloperoxidase from neutrophil granules. [31] When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme uses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach. Hypochlorite is extremely toxic to bacteria. [2] Myeloperoxidase contains a heme pigment, which accounts for the green color of secretions rich in neutrophils, such as pus and infected sputum. [32]

Oxygen-independent intracellular Edit

Phagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as the oxygen-dependent ones. There are four main types. The first uses electrically charged proteins that damage the bacterium's membrane. The second type uses lysozymes these enzymes break down the bacterial cell wall. The third type uses lactoferrins, which are present in neutrophil granules and remove essential iron from bacteria. [33] The fourth type uses proteases and hydrolytic enzymes these enzymes are used to digest the proteins of destroyed bacteria. [34]

Extracellular Edit

Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4 + T cells, CD8 + T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. [35] Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. [2] Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule [36] —kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. [37]

In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. [38] In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chédiak–Higashi syndrome, are also associated with defective killing of ingested microbes. [39]

Viruses Edit

Viruses can reproduce only inside cells, and they gain entry by using many of the receptors involved in immunity. Once inside the cell, viruses use the cell's biological machinery to their own advantage, forcing the cell to make hundreds of identical copies of themselves. Although phagocytes and other components of the innate immune system can, to a limited extent, control viruses, once a virus is inside a cell the adaptive immune responses, particularly the lymphocytes, are more important for defense. [40] At the sites of viral infections, lymphocytes often vastly outnumber all the other cells of the immune system this is common in viral meningitis. [41] Virus-infected cells that have been killed by lymphocytes are cleared from the body by phagocytes. [42]

In an animal, cells are constantly dying. A balance between cell division and cell death keeps the number of cells relatively constant in adults. [12] There are two different ways a cell can die: by necrosis or by apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmed cell death—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cells every day, and phagocytes play a crucial role in this process. [43]

Dying cells that undergo the final stages of apoptosis [44] display molecules, such as phosphatidylserine, on their cell surface to attract phagocytes. [45] Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase. [46] [47] These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages. [48] The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response and is an important function of phagocytes. [49]

Phagocytes are usually not bound to any particular organ but move through the body interacting with the other phagocytic and non-phagocytic cells of the immune system. They can communicate with other cells by producing chemicals called cytokines, which recruit other phagocytes to the site of infections or stimulate dormant lymphocytes. [50] Phagocytes form part of the innate immune system, which animals, including humans, are born with. Innate immunity is very effective but non-specific in that it does not discriminate between different sorts of invaders. On the other hand, the adaptive immune system of jawed vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any type of invader. [51] The adaptive immune system is not dependent on phagocytes but lymphocytes, which produce protective proteins called antibodies, which tag invaders for destruction and prevent viruses from infecting cells. [52] Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen presentation. [53]

Antigen presentation Edit

Antigen presentation is a process in which some phagocytes move parts of engulfed materials back to the surface of their cells and "present" them to other cells of the immune system. [54] There are two "professional" antigen-presenting cells: macrophages and dendritic cells. [55] After engulfment, foreign proteins (the antigens) are broken down into peptides inside dendritic cells and macrophages. These peptides are then bound to the cell's major histocompatibility complex (MHC) glycoproteins, which carry the peptides back to the phagocyte's surface where they can be "presented" to lymphocytes. [15] Mature macrophages do not travel far from the site of infection, but dendritic cells can reach the body's lymph nodes, where there are millions of lymphocytes. [56] This enhances immunity because the lymphocytes respond to the antigens presented by the dendritic cells just as they would at the site of the original infection. [57] But dendritic cells can also destroy or pacify lymphocytes if they recognize components of the host body this is necessary to prevent autoimmune reactions. This process is called tolerance. [58]

Immunological tolerance Edit

Dendritic cells also promote immunological tolerance, [59] which stops the body from attacking itself. The first type of tolerance is central tolerance, that occurs in the thymus. T cells that bind (via their T cell receptor) to self antigen (presented by dendritic cells on MHC molecules) too strongly are induced to die. The second type of immunological tolerance is peripheral tolerance. Some self reactive T cells escape the thymus for a number of reasons, mainly due to the lack of expression of some self antigens in the thymus. Another type of T cell T regulatory cells can down regulate self reactive T cells in the periphery. [60] When immunological tolerance fails, autoimmune diseases can follow. [61]

Phagocytes of humans and other jawed vertebrates are divided into "professional" and "non-professional" groups based on the efficiency with which they participate in phagocytosis. [9] The professional phagocytes are the monocytes, macrophages, neutrophils, tissue dendritic cells and mast cells. [10] One litre of human blood contains about six billion phagocytes. [5]

Activation Edit

All phagocytes, and especially macrophages, exist in degrees of readiness. Macrophages are usually relatively dormant in the tissues and proliferate slowly. In this semi-resting state, they clear away dead host cells and other non-infectious debris and rarely take part in antigen presentation. But, during an infection, they receive chemical signals—usually interferon gamma—which increases their production of MHC II molecules and which prepares them for presenting antigens. In this state, macrophages are good antigen presenters and killers. However, if they receive a signal directly from an invader, they become "hyperactivated", stop proliferating, and concentrate on killing. Their size and rate of phagocytosis increases—some become large enough to engulf invading protozoa. [62]

In the blood, neutrophils are inactive but are swept along at high speed. When they receive signals from macrophages at the sites of inflammation, they slow down and leave the blood. In the tissues, they are activated by cytokines and arrive at the battle scene ready to kill. [63]

Migration Edit

When an infection occurs, a chemical "SOS" signal is given off to attract phagocytes to the site. [64] These chemical signals may include proteins from invading bacteria, clotting system peptides, complement products, and cytokines that have been given off by macrophages located in the tissue near the infection site. [2] Another group of chemical attractants are cytokines that recruit neutrophils and monocytes from the blood. [13]

To reach the site of infection, phagocytes leave the bloodstream and enter the affected tissues. Signals from the infection cause the endothelial cells that line the blood vessels to make a protein called selectin, which neutrophils stick to on passing by. Other signals called vasodilators loosen the junctions connecting endothelial cells, allowing the phagocytes to pass through the wall. Chemotaxis is the process by which phagocytes follow the cytokine "scent" to the infected spot. [2] Neutrophils travel across epithelial cell-lined organs to sites of infection, and although this is an important component of fighting infection, the migration itself can result in disease-like symptoms. [65] During an infection, millions of neutrophils are recruited from the blood, but they die after a few days. [66]

Monocytes Edit

Monocytes develop in the bone marrow and reach maturity in the blood. Mature monocytes have large, smooth, lobed nuclei and abundant cytoplasm that contains granules. Monocytes ingest foreign or dangerous substances and present antigens to other cells of the immune system. Monocytes form two groups: a circulating group and a marginal group that remain in other tissues (approximately 70% are in the marginal group). Most monocytes leave the blood stream after 20–40 hours to travel to tissues and organs and in doing so transform into macrophages [67] or dendritic cells depending on the signals they receive. [68] There are about 500 million monocytes in one litre of human blood. [5]

Macrophages Edit

Mature macrophages do not travel far but stand guard over those areas of the body that are exposed to the outside world. There they act as garbage collectors, antigen presenting cells, or ferocious killers, depending on the signals they receive. [69] They derive from monocytes, granulocyte stem cells, or the cell division of pre-existing macrophages. [70] Human macrophages are about 21 micrometers in diameter. [71]

This type of phagocyte does not have granules but contains many lysosomes. Macrophages are found throughout the body in almost all tissues and organs (e.g., microglial cells in the brain and alveolar macrophages in the lungs), where they silently lie in wait. A macrophage's location can determine its size and appearance. Macrophages cause inflammation through the production of interleukin-1, interleukin-6, and TNF-alpha. [72] Macrophages are usually only found in tissue and are rarely seen in blood circulation. The life-span of tissue macrophages has been estimated to range from four to fifteen days. [73]

Macrophages can be activated to perform functions that a resting monocyte cannot. [72] T helper cells (also known as effector T cells or Th cells), a sub-group of lymphocytes, are responsible for the activation of macrophages. Th1 cells activate macrophages by signaling with IFN-gamma and displaying the protein CD40 ligand. [74] Other signals include TNF-alpha and lipopolysaccharides from bacteria. [72] Th1 cells can recruit other phagocytes to the site of the infection in several ways. They secrete cytokines that act on the bone marrow to stimulate the production of monocytes and neutrophils, and they secrete some of the cytokines that are responsible for the migration of monocytes and neutrophils out of the bloodstream. [75] Th1 cells come from the differentiation of CD4 + T cells once they have responded to antigen in the secondary lymphoid tissues. [72] Activated macrophages play a potent role in tumor destruction by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, cationic proteins, and hydrolytic enzymes. [72]

Neutrophils Edit

Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells. [76] One litre of human blood contains about five billion neutrophils, [5] which are about 10 micrometers in diameter [77] and live for only about five days. [37] Once they have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection. [78] They are ferocious eaters and rapidly engulf invaders coated with antibodies and complement, and damaged cells or cellular debris. Neutrophils do not return to the blood they turn into pus cells and die. [78] Mature neutrophils are smaller than monocytes and have a segmented nucleus with several sections each section is connected by chromatin filaments—neutrophils can have 2–5 segments. Neutrophils do not normally exit the bone marrow until maturity but during an infection neutrophil precursors called metamyelocytes, myelocytes and promyelocytes are released. [79]

The intra-cellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties. [80] Neutrophils can secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing. [81] Secretions from the primary granules of neutrophils stimulate the phagocytosis of IgG-antibody-coated bacteria. [82]

Dendritic cells Edit

Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites, [83] that help to engulf microbes and other invaders. [84] [85] Dendritic cells are present in the tissues that are in contact with the external environment, mainly the skin, the inner lining of the nose, the lungs, the stomach, and the intestines. [86] Once activated, they mature and migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and orchestrate the adaptive immune response. [87] Mature dendritic cells activate T helper cells and cytotoxic T cells. [88] The activated helper T cells interact with macrophages and B cells to activate them in turn. In addition, dendritic cells can influence the type of immune response produced when they travel to the lymphoid areas where T cells are held they can activate T cells, which then differentiate into cytotoxic T cells or helper T cells. [84]

Mast cells Edit

Mast cells have Toll-like receptors and interact with dendritic cells, B cells, and T cells to help mediate adaptive immune functions. [89] Mast cells express MHC class II molecules and can participate in antigen presentation however, the mast cell's role in antigen presentation is not very well understood. [90] Mast cells can consume and kill gram-negative bacteria (e.g., salmonella), and process their antigens. [91] They specialize in processing the fimbrial proteins on the surface of bacteria, which are involved in adhesion to tissues. [92] [93] In addition to these functions, mast cells produce cytokines that induce an inflammatory response. [94] This is a vital part of the destruction of microbes because the cytokines attract more phagocytes to the site of infection. [91] [95]

Professional Phagocytes [96]
Main location Variety of phenotypes
Blood neutrophils, monocytes
Bone marrow macrophages, monocytes, sinusoidal cells, lining cells
Bone tissue osteoclasts
Gut and intestinal Peyer's patches macrophages
Connective tissue histiocytes, macrophages, monocytes, dendritic cells
Liver Kupffer cells, monocytes
Lung self-replicating macrophages, monocytes, mast cells, dendritic cells
Lymphoid tissue free and fixed macrophages and monocytes, dendritic cells
Nervous tissue microglial cells (CD4 + )
Spleen free and fixed macrophages, monocytes, sinusoidal cells
Thymus free and fixed macrophages and monocytes
Skin resident Langerhans cells, other dendritic cells, conventional macrophages, mast cells

Dying cells and foreign organisms are consumed by cells other than the "professional" phagocytes. [97] These cells include epithelial cells, endothelial cells, fibroblasts, and mesenchymal cells. They are called non-professional phagocytes, to emphasize that, in contrast to professional phagocytes, phagocytosis is not their principal function. [98] Fibroblasts, for example, which can phagocytose collagen in the process of remolding scars, will also make some attempt to ingest foreign particles. [99]

Non-professional phagocytes are more limited than professional phagocytes in the type of particles they can take up. This is due to their lack of efficient phagocytic receptors, in particular opsonins—which are antibodies and complement attached to invaders by the immune system. [11] Additionally, most nonprofessional phagocytes do not produce reactive oxygen-containing molecules in response to phagocytosis. [100]

Non-professional Phagocytes [96]
Main location Variety of phenotypes
Blood, lymph and lymph nodes Lymphocytes
Blood, lymph and lymph nodes NK and LGL cells (large granular lymphocytes)
Blood Eosinophils and Basophils [101]
Skin Epithelial cells
Blood vessels Endothelial cells
Connective tissue Fibroblasts

A pathogen is only successful in infecting an organism if it can get past its defenses. Pathogenic bacteria and protozoa have developed a variety of methods to resist attacks by phagocytes, and many actually survive and replicate within phagocytic cells. [102] [103]

Avoiding contact Edit

There are several ways bacteria avoid contact with phagocytes. First, they can grow in sites that phagocytes are not capable of traveling to (e.g., the surface of unbroken skin). Second, bacteria can suppress the inflammatory response without this response to infection phagocytes cannot respond adequately. Third, some species of bacteria can inhibit the ability of phagocytes to travel to the site of infection by interfering with chemotaxis. [102] Fourth, some bacteria can avoid contact with phagocytes by tricking the immune system into "thinking" that the bacteria are "self". Treponema pallidum—the bacterium that causes syphilis—hides from phagocytes by coating its surface with fibronectin, [104] which is produced naturally by the body and plays a crucial role in wound healing. [105]

Avoiding engulfment Edit

Bacteria often produce capsules made of proteins or sugars that coat their cells and interfere with phagocytosis. [102] Some examples are the K5 capsule and O75 O antigen found on the surface of Escherichia coli, [106] and the exopolysaccharide capsules of Staphylococcus epidermidis. [107] Streptococcus pneumoniae produces several types of capsule that provide different levels of protection, [108] and group A streptococci produce proteins such as M protein and fimbrial proteins to block engulfment. Some proteins hinder opsonin-related ingestion Staphylococcus aureus produces Protein A to block antibody receptors, which decreases the effectiveness of opsonins. [109] Enteropathogenic species of the genus Yersinia bind with the use of the virulence factor YopH to receptors of phagocytes from which they influence the cells capability to exert phagocytosis. [110]

Survival inside the phagocyte Edit

Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system. [111] To get safely inside the phagocyte they express proteins called invasins. When inside the cell they remain in the cytoplasm and avoid toxic chemicals contained in the phagolysosomes. [112] Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. [102] Other pathogens, such as Leishmania, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate. [113] Some bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus, for example, produces the enzymes catalase and superoxide dismutase, which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria. [114] Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using enzymes called listeriolysin O and phospholipase C. [115]

Killing Edit

Bacteria have developed several ways of killing phagocytes. [109] These include cytolysins, which form pores in the phagocyte's cell membranes, streptolysins and leukocidins, which cause neutrophils' granules to rupture and release toxic substances, [116] [117] and exotoxins that reduce the supply of a phagocyte's ATP, needed for phagocytosis. After a bacterium is ingested, it may kill the phagocyte by releasing toxins that travel through the phagosome or phagolysosome membrane to target other parts of the cell. [102]

Disruption of cell signaling Edit

Some survival strategies often involve disrupting cytokines and other methods of cell signaling to prevent the phagocyte's responding to invasion. [118] The protozoan parasites Toxoplasma gondii, Trypanosoma cruzi, and Leishmania infect macrophages, and each has a unique way of taming them. [118] Some species of Leishmania alter the infected macrophage's signalling, repress the production of cytokines and microbicidal molecules—nitric oxide and reactive oxygen species—and compromise antigen presentation. [119]

Macrophages and neutrophils, in particular, play a central role in the inflammatory process by releasing proteins and small-molecule inflammatory mediators that control infection but can damage host tissue. In general, phagocytes aim to destroy pathogens by engulfing them and subjecting them to a battery of toxic chemicals inside a phagolysosome. If a phagocyte fails to engulf its target, these toxic agents can be released into the environment (an action referred to as "frustrated phagocytosis"). As these agents are also toxic to host cells, they can cause extensive damage to healthy cells and tissues. [120]

When neutrophils release their granule contents in the kidney, the contents of the granule (reactive oxygen compounds and proteases) degrade the extracellular matrix of host cells and can cause damage to glomerular cells, affecting their ability to filter blood and causing changes in shape. In addition, phospholipase products (e.g., leukotrienes) intensify the damage. This release of substances promotes chemotaxis of more neutrophils to the site of infection, and glomerular cells can be damaged further by the adhesion molecules during the migration of neutrophils. The injury done to the glomerular cells can cause kidney failure. [121]

Neutrophils also play a key role in the development of most forms of acute lung injury. [122] Here, activated neutrophils release the contents of their toxic granules into the lung environment. [123] Experiments have shown that a reduction in the number of neutrophils lessens the effects of acute lung injury, [124] but treatment by inhibiting neutrophils is not clinically realistic, as it would leave the host vulnerable to infection. [123] In the liver, damage by neutrophils can contribute to dysfunction and injury in response to the release of endotoxins produced by bacteria, sepsis, trauma, alcoholic hepatitis, ischemia, and hypovolemic shock resulting from acute hemorrhage. [125]

Chemicals released by macrophages can also damage host tissue. TNF-α is an important chemical that is released by macrophages that causes the blood in small vessels to clot to prevent an infection from spreading. [126] However, if a bacterial infection spreads to the blood, TNF-α is released into vital organs, which can cause vasodilation and a decrease in plasma volume these in turn can be followed by septic shock. During septic shock, TNF-α release causes a blockage of the small vessels that supply blood to the vital organs, and the organs may fail. Septic shock can lead to death. [13]

Phagocytosis is common and probably appeared early in evolution, [127] evolving first in unicellular eukaryotes. [128] Amoebae are unicellular protists that separated from the tree leading to metazoa shortly after the divergence of plants, and they share many specific functions with mammalian phagocytic cells. [128] Dictyostelium discoideum, for example, is an amoeba that lives in the soil and feeds on bacteria. Like animal phagocytes, it engulfs bacteria by phagocytosis mainly through Toll-like receptors, and it has other biological functions in common with macrophages. [129] Dictyostelium discoideum is social it aggregates when starved to form a migrating pseudoplasmodium or slug. This multicellular organism eventually will produce a fruiting body with spores that are resistant to environmental dangers. Before the formation of fruiting bodies, the cells will migrate as a slug-like organism for several days. During this time, exposure to toxins or bacterial pathogens has the potential to compromise survival of the species by limiting spore production. Some of the amoebae engulf bacteria and absorb toxins while circulating within the slug, and these amoebae eventually die. They are genetically identical to the other amoebae in the slug their self-sacrifice to protect the other amoebae from bacteria is similar to the self-sacrifice of phagocytes seen in the immune system of higher vertebrates. This ancient immune function in social amoebae suggests an evolutionarily conserved cellular foraging mechanism that might have been adapted to defense functions well before the diversification of amoebae into higher forms. [130] Phagocytes occur throughout the animal kingdom, [3] from marine sponges to insects and lower and higher vertebrates. [131] [132] The ability of amoebae to distinguish between self and non-self is a pivotal one, and is the root of the immune system of many species of amoeba. [8]

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Immunity and Your Immune System

The immune system is a complex network of cells, tissues and organs that has evolved to protect us against the constant challenges we face every day. These challenges include billions of germs, pollution and even the effects of physical and psychological stress. Sometimes these challenges overwhelm our immune system and we become ill.

The human immune system can be broadly segregated into two parts: innate immune system and the adaptive immune system. The 'innate' (meaning: "present from birth") part of the immune system is so-called because it has a number of set strategies for recognizing and destroying challenges, without needing to be trained to identify them. The adaptive immune system isn't able to respond instantly to challenges, as it needs time to adapt (or learn) to recognize them. Once it has learned, however, it is extremely effective and is also able to remember particular pathogens that have previously infected the body, so that when (or if) they try to infect the body again, the next response is rapid, accurate, and effective.

The adaptive (also called the specific) immune system is composed of lymphocyte cells (B and T cells) that can learn to identify pathogens and provide with a specific response to kill the pathogen. Adaptive immune cells produce soluble factors, such as antibodies, which neutralize the ability of pathogens to infect the host and antibodies also enhance the antimicrobial activities of phagocytes. The ability to produce antibodies to kill a specific pathogen is a learned or memory response and takes years to fully develop.

Innate immunity is something already present in the body. As soon as something enters the skin, blood, or tissues, the immune system immediately goes into attack mode. The innate immune system is composed of phagocytic cells that engulf (eat) pathogens, other immune cells that release chemicals (oxidative burst) to kill pathogens and soluble factors, such as complement, which have antibacterial properties on their own or that enhance the antimicrobial activities of phagocytes. Generally, innate immune cells migrate to sites of challenges via the bloodstream, and neutralizing the pathogens by engulfing them and killing them with special chemicals (a process known as phagocytosis). Complement is used by the human immune system to label and identify pathogenic cells so that these can be phagocytosed.

There are differences between innate and adaptive immune systems, but they both work together for the same function by keeping us healthy.

Wellmune, the key ingredient in Immune Health Basics supplements, activates innate immune cells, which are part of the body's firstline of defense to keep you healthy without overstimulating your body&rsquos immune system.