Blood and Immunity - Week 8

Question 1

What does exposure to a microbe give?

Answer 1

• The first exposure of the body to a microbe gives a primary immune response, so the response is generated against that microbe to which the body is exposed, and this induces immunological memory.
• This means the body maintains a memory of having been exposed to the components of that particular microbe, but if it’s re-exposed to that microbe, it can then make a secondary or adaptive response, which is more efficient and better at protecting the body against that infecting microbe.
• So, this process of vaccination demonstrates a fundamental property of the human immune system that we call adaptive immunity, this
  ability of the immune system to adapt to having made an immune response to the components of a particular microbe, such that if the body is re-exposed to that same microbe, it actually makes a better and more efficient response which is then protective against that particular infectious disease.
• The property of adaptive immunity is generated in the body by one of particular type of white blood cells called lymphocytes.

Question 2

What do lymphocytes derive from?

Answer 2

• The lymphocytes like all the white blood cells, and the red blood cells, all the cell types that circulate in the blood stream, arise from stem cells which are found in the bone marrow.
• So the bone marrow is one of the primary lymphoid organs, because it’s one of the organs in which lymphocytes, as well as all the other leukocytes, develop from stem cell precursors.

Question 3

What are the two types of lymphocytes in humans?

Answer 3

-In humans, there are two types of lymphocytes.
-One of these undergoes its full development in the bone marrow, and these are
called B lymphocytes, but for the other type of lymphocytes, their precursors, once they’ve been formed from stem cells, leave the bone marrow, circulate around body, and enter tissue of organ called the thymus, which is found in the top of the chest, and it’s
there they undergo their full development, and these are referred to as T lymphocytes.
-So B lymphocytes develop in bone marrow, and T lymphocytes develop in the thymus, and those are the two primary lymphoid organs.
-Once mature B and T lymphocytes have been formed, they circulate around the body in the blood stream, and can enter and spend some time in a whole range of what are called secondary lymphoid tissues.
-Mature circulating lymphocytes accumulate
here.

Question 4

What are secondary lympoid tissues?

Answer 4

-Secondary lymphoid tissues include the diverse network of lymph nodes found throughout the body, the spleen, and then there are
large amounts of lymphoid tissue associated with all the mucosal tissues of the body, these are the so called mucosa associated
lymphoid tissues, and are found in the lymphoid tract, the GI tract and the urinogenital tract.
-They include bronchus associated lymphoid tissue in the lungs, and then in the GI tract, there are tissues called Peyer’s patches, lamina propria and the appendix.

Question 5

How do lymphocytes circulate around the body?

Answer 5

-Lymphocytes circulate around body in blood stream and can leave blood to pass into other tissues.
-Some lymphocytes can leave
blood stream and enter for example tissue of spleen, spend some time there, maybe 1 to 2 days, and then directly re-enter the blood circulation.
-Lymphocytes can also leave blood stream and enter tissues of lymph nodes and spend some time in lymph
nodes.
-Also, another route which by lymphocytes can migrate into lymph nodes, and this is an indirect route via peripheral tissue.
-This refers to any other tissues of body which are not specialised lymphoid tissues, but all the tissues into which lymphocytes can pass at a low but continuous rate from the blood stream into the tissues.
-Then those lymphocytes that have entered all tissues of the body, leave in the tissue fluid which migrates into afferent lymphatics, afferent means carrying towards the lymph nodes.
-So, these lymphocytes in the afferent lymphatics are also carried into lymph nodes from the other tissues they’d entered.
-The majority of lymphocytes found in a lymphocyte at any point in time have actually
arrived there direct from the blood stream, but the rest have arrived from other peripheral tissues via the afferent lymphatics.
-Usually after just one to days after being in lymph node, lymphocytes then gradually migrate out of lymph nodes into efferent lymphatics, efferent meaning to carry away from the lymph nodes, and most of these then re-enter blood circulation at the major junction between lymphatic system and the blood circulatory system, at what’s called the thoracic duct, and they can circulate
around body again.
-So, this continual circulation of lymphocytes around body via blood stream and lymphatic system shows
they’re able to survey whole of body for potential infection.

Question 6

What different infectious agents are in the body?

Answer 6

• Variety of infectious agents which can cause infectious disease in humans.
• There are viruses, bacteria, fungi, single celled protozoa parasites, and multicellular parasitic worms or helminths that can cause human infections.
• Have many different biological
  characteristics.
• This complexity of the world of infectious agents that can cause human disease, means the immune system itself has to be relatively complex in order to deal with all these infections.
• This is because the types of processes that are necessary to, for example, protect body against viruses, are not the same in all instances, as the processes needed to protect the body from bacteria for example.
• This complexity of the immune system is partly shown in the variety of cell types involved within immune system.

Question 7

What are the cell mediators of immunity?

Answer 7

Neutrophils, eosinophils, basophils, mast cells, monocytes which differentiate into macrophages, dendritic cells, NK cells which stand for natural killer cells, T cells and B cells.

Question 8

What are the two types of T lymphocytes?

Answer 8

-There are two major functional types of T cells, the CD4^+ Th lymphocytes and CD8^+ Tc lymphocytes.
- T helper cells have the job
of helping to activate other cells of the immune system. The Tc cells, the C stands for cytotoxic, so the job of the cytotoxic T cells is to kill other cells of the body, in particular to kill infected cells.

Question 9

Which are the granulocytes?

Answer 9

-Eosinophils, neutrophils, basophils and mast cells in particular are also known as granulocytes, as contain distinctive granules in their cytoplasm, and the histological dyes that stain the granules in those different cells give rise to their names.
-Neutrophils in particular also know as polymorphonuclear leucocytes, PMN leucocytes, polymorphonuclear meaning they have nuclei which have a lobulated shape with various arms.
- Neutrophils, eosinophils and basophils, principle is circulation in blood stream,
whereas mast cells, are tissue resident cells, rather than circulating cells.

Question 10

Which are the mononuclear cells?

Answer 10

-Monocytes, macrophages, dendritic cells, NK cells, Tc lymphocytes, Th lymphocytes and B lymphocytes are mononuclear cells, as have relatively smooth rounded shape nuclei.
-Monocytes are circulating cells found in blood, but can migrate out of blood into
tissues, where they differentiate into macrophages.
-Then have dendritic cells, which can have long arm like or dendrite processes.

Question 11

Which are myeloid cells?

Answer 11

Have myeloid cells, derived from myeloid stem cells, so that includes neutrophils, eosinophils, basophils, mast cells, monocytes, macrophages and some of the dendritic cells.

Question 12

Which are lymphoid cells?

Answer 12

NK cells, B lymphocytes, T lymphocytes and some of the dendritic cells.

Question 13

What are secreted mediators of immunity?

Answer 13

-As well as all the different cell types, have whole host of soluble molecules referred to as secreted mediators of immunity that can be released by various cell types to mediate roles within immune responses.
-Most are various types of proteins, only exceptions
are the prostaglandins and leukotrienes which are not proteins, they are chemically derived from arachidonic acid, and histamine is also not a protein.

Question 14

What are functions of anti-microbial mediators?

Answer 14

Have direct protective effects in immune response, so have anti-microbial effects in terms of helping to destroy and eliminate microbes from body.

Question 15

What are the functions of regulatory/ inflammatory

secreted mediators?

Answer 15

-Roles in regulating the immune response, so controlling the occurrence and the size of immune responses.
-As well as thinking of
regulation, also use word inflammatory.
- In physiological terms, inflammation is an essential part of immune response as it refers to all those processes which enable all the cells and molecules to get to sites of infection.
-The inflammation associated with an infection is the drawing of all these cells and molecules to where the infecting microbes are in order to bring about the immune response and elimination of the infection.
-Examples are cytokines (e.g. interleukins, interferons), chemokines, prostaglandins, leukotrienes (products of arachidonic acid) and histamine.

Question 16

Which cell mediators are adaptive?

Answer 16

Adaptive immunity is the property of the T and B lymphocytes and the ability of the immune system to adapt to having made a response to a particular invading microbe, such as if there’s re-exposure to that microbe, a better and more efficient response can
then be generated, which is more protective.

Question 17

Which cell mediators are innate?

Answer 17

-These generate innate immunity.
-These are neutrophils, eosinophils, basophils, mast cells, monocytes, macrophages, dendritic
cells and NK cells.

Question 18

What is an advantage of innate immunity?

Answer 18

• The advantage is that it is very rapidly activated when infection, when microbes, come into body.
• So, within minutes of microbes infecting a tissue, there is triggering of the processes we define as innate immunity.

Question 19

What is a disadvantage of innate immunity?

Answer 19

• It doesn’t learn from this activation, unlike adaptive immunity.
• In terms of repeated infection by the same type of microbe, the innate immunity is pretty much the same on each occasion, it doesn’t improve upon that repeated exposure to the microbe.

Question 20

What does it mean that innate immunity is moderately efficient?

Answer 20

-Innate immunity is moderately efficient, meaning although on a day-to-day basis in terms of just general exposure to common environmental microbes, innate immunity is good at ensuring we are not too affected by those microbes and the infection they could potentially cause.
-But when we’re exposed to a very virulent, a very pathogenic disease causing microbe, innate immunity
on its own is unlikely to be sufficient to give us complete protection against that microbe.

Question 21

How does innate immunity recognise presence of

infection and respond to it?

Answer 21

In terms of how innate immunity recognises the presence of infection and responds to it, so the recognition processes, in general terms, innate immunity can make a general response to categories of microbe, meaning we think of a macrophage as one of the
cells types involved in generating innate immunity, then macrophages can look at a microbe and say this is some kind of bacterium, so need to react to it in this sort of way, or alternatively, actually it is some sort of virus, so need to generate this type of
response which is going to be more effective against viruses, but can’t do much more than that.

Question 22

What chemical processes are involved in recognition of infection?

Answer 22

-In terms of chemical processes involved in recognition of infection, what we say in terms of innate immunity, is that cells such as
macrophages recognise chemical constituents of infecting microbes that we call pathogen associated molecular patterns, PAMPs.
-This means that these are chemical structures of the microbes, the pathogens, the disease-causing agents, which distinguish them from anything that is naturally part of our own bodies, so chemical made by the microbes that we can think of as foreign to our cells.
-For example, one is bacterial lipopolysaccharide, so bacteria have lipopolysaccharide as an important component of their surface structures.
- Our own cells don’t make lipopolysaccharides of the type found in bacteria, so that is a chemical, a molecular pattern
which distinguishes bacteria as something foreign to our cells.
-Another example is viral double-stranded RNA.
-We make lots of RNA, but all our RNA is single stranded, so the fact that viruses in some circumstances make double stranded RNA, means that
can be a molecular pattern that indicates the presence of infecting viruses in the body.

Question 23

How are PAMPs recognised?

Answer 23

• These PAMPs are recognised by binding to surface molecules and in some cases cytoplasmic molecules of cells involved in innate immunity, called pattern recognition receptors, PRRs.
• These are molecules expressed by the innate immunity cells, which bind to the PAMPs.
• So there are pattern recognition receptors that bind to bacterial lipopolysaccharide, there are others that can bind to viral double-stranded RNA, and so on.

Question 24

What are the PRRs like expressed on the surface?

Answer 24

Taking macrophages as an example, each will have a whole host of PRRs, but each macrophage will have a very similar set of PRRs, so they would all be able to bind a particular PAMP.

Question 25

What is adaptive immunity?

Answer 25

- Adaptive immunity can also be called acquired immunity, immunity that’s acquired as a consequence of being exposed to a particular microbe. - It’s the type of immunity generated by the T and B lymphocytes.

Question 26

What is a disadvantage of adaptive immunity?

Answer 26

Downside is that it’s relatively slowly activated, it takes days to activate lymphocytes against a particular type of infection.

Question 27

What is an advantage of adaptive immunity?

Answer 27

- It improves and becomes more efficient on repeated exposure to the same microbe. - This is a property of the immune system which is taken advantage of in the process of vaccination.

Question 28

How does adaptive immunity have high efficiency?

Answer 28

-Once lymphocytes are activated against the microbes, they can be much more efficient than innate immunity in eliminating them from the body. -Part of the reason for this higher efficiency of adaptive immunity is the way that lymphocytes recognise constituents of microbes. -Innate immunity can just distinguish general categories of microbes, so viruses or bacteria, whereas lymphocytes can very specifically recognise different microbes through responses that are tailored to the individual types of microbes. -So, lymphocytes collectively can not only recognise something as a bacterium, but sub species of those. -Reason for those high efficiency and specificity of recognition of microbes is because of the different way in which lymphocytes recognise components of microbes as compared with innate immune cells.

Question 29

How are microbes recognised in adaptive immunity as opposed to innate?

Answer 29

- So rather than recognising PAMPs, the constituents of microbes recognised by lymphocytes are called antigens. - An antigen is any constituent of a microbe which can be specifically recognised by a lymphocyte, and therefore the recognition of these antigens is achieved by antigen specific receptors, molecules expressed on the surface of lymphocytes which specifically bind to particular antigens of infecting microbes.

Question 30

What is meant by specific antigen recognition?

Answer 30

-For example, different B lymphocytes from all over the body each have different surface antigen receptors. -Each would express several thousand receptors on its surface. - All of these receptors have exactly the same structure on a single lymphocyte, and structure is different from receptors found on another lymphocyte. -So, each lymphocyte therefore has a receptor for recognising only a single antigen out of all the potential millions of antigens microbes are made up from. -So, if have one single antigen would expect that only one lymphocyte has the right shaped antigen receptor to bind to that particular antigen, that’s what’s meant by specific antigen recognition. -Reason why then lymphocytes collectively can recognise potentially millions of different antigens as found as constituents of microbes is we have billions of lymphocytes in our body, and collectively therefore they express millions of different antigen receptors.

Question 31

What are the stages of a primary immune response?

Answer 31

-A simple immune response for a skin infection for example, would include an epithelial barrier, an immediate local innate response, early induced innate/ inflammatory response and a later adaptive response. -Have bacteria sitting on surface of skin. -Skin becomes cut, meaning bacteria can get through the hard keratinised surface that they can’t normally penetrate and get into the underlying softer dermal tissues. -Now in a nutritious environment where can start to replicate. -So bacteria has penetrated the surface epithelial barriers of the body. -As soon as bacteria have entered the dermal tissues and started to replicate will have immediately come into contact with components that can generate innate immunity. -So, this will include macrophages, that express the pattern recognition receptors that can bind to PAMPs of those bacteria. -Also, soluble proteins called complement proteins, some of which can also bind to the surface of the bacteria. -So, this triggers activation of cells like macrophages and complement proteins generating the initial innate immune response. - This can immediately start to bring about damage to the bacteria. -The immediate local response outlined above leads to the production of a host of chemical called inflammatory mediators. -Some of these will be produced by the activated macrophages, some by activated complement proteins, and in addition in this context, are inflammatory mediators made by those cells called the mast cells. -What these inflammatory mediators do is activate the walls of nearby blood vessels, making them leaky, allowing more leucocytes and fluids carrying complement proteins to leave the blood stream and enter the infected tissue. -So, these are the processes referred to as inflammatory processes, and is the way in which more cells and molecules of the immune system can be brought into the site of infection in order to fight it. -While all of that initial innate response is happening, processes are also being set in train to generate the adaptive immune response to this infection. - This doesn’t happen initially at the site of infection itself, what happens is some of the components of the infecting microbes that in the context of the adaptive response we can think of as antigens, are carried from the site of infection to a draining lymph node by being carried into the afferent lymphatics that take fluid and cells to that lymph node. -Some of the antigens are carried free and soluble in the lymphatic fluid, others are captured by those specialised cells called the dendritic cells, and they migrate into the afferent lymphatics, carrying the antigens with them to the lymph node. -So, it’s there in the lymph node, that the lymphocytes are located which have antigen specific receptors that can bind to the particular antigens derived from this particular infecting microbe. -So there the T and B lymphocytes become activated, this takes a few days to happen, then once activated, those T and B lymphocytes can leave the lymph node, go back into the blood stream, and recirculate back to the site of infection. -This is why it takes quite a lot more time to generate the adaptive than the immediate innate response.

Question 32

What happens following primary infection?

Answer 32

-Some of those activated B lymphocytes, rather than actually getting involved in this primary response to this microbe, will actually become the memory T and B cells, which carry with them the memory of being activated by those antigens. -So, if at some future time there’s a second infection with this same type of microbe, so the same antigens are brought into the body, those memory T and B cells can be reactivated and their reactivation is faster and gives a bigger response on second occasion, hence showing the properties of adaptive immunity.

Question 33

How does the immune system respond to different categories of infection?

Answer 33

-Differences in immune responses to bacteria and viruses and so on. -The most important thing to the immune system is not the nature of the infecting pathogen, it’s how and where it affects the body and where it locates, in particular whether once it gets into the tissues of the body, the infecting agent stays outside the cells, what we call an extracellular infection, or actually goes through the surface membrane of cells, into the cytoplasm, and becomes an intracellular infection, because then the immune system has to use different types of strategies to deal with the infection depending on whether it’s extracellular or intracellular. -In case of extracellular infection, for example many types of bacteria, those extracellular microbes remain exposed to anything from the immune system that can bind to their surfaces, including the complement proteins, phagocytes like macrophages, and specialised proteins called antibodies made by B lymphocytes. -

Question 34

How does the immune system respond to intracellular vesicular infections?

Answer 34

-Sometimes when microbes are deliberately engulfed by macrophages, this is a way in which macrophages kill microbes by engulfing them, they take them into membrane bound vesicles in their cytoplasm, with attention of then digesting the microbes, but some microbes are very resistant to being digested in vesicles in macrophages. -So, what immune system has to do, is to try to hyperactivate the macrophages to overcome resistance of microbes to being digested, and this is achieved by activating signals delivered to the macrophages by the helper T lymphocytes.

Question 35

How does the immune system respond to intracellular cytosolic infections?

Answer 35

-This is where there are microbes in the fluid phase of the cytoplasm rather than being present in vesicles, and this category of infection applies in particular to all types of viruses, because viruses infect cells of the body and use the machinery of those cells to replicate, so immune system has to then target those infected cells to try and limit the replication of viruses within them. -So, one mechanism to use proteins called interferons, which block the ability of the viruses to replicate in cells. -The other category of mechanism here is to kill the infected cells, as viruses can’t replicate in a dead cell, so the virus infected cells are targeted by the natural killer cells, and the cytotoxic T lymphocytes and these then kill virus infected cells to limit the replication.

Question 36

What is immunopathology?

Answer 36

- Immunopathology deals with diseases, pathological conditions, caused by defects in, or inappropriate behaviour of the immune system. - Main categories of immunopathological disorders include immunodeficiency, allergy, autoimmunity, transplant rejection and lymphoproliferative diseases.

Question 37

What is immunodeficiency?

Answer 37

Immunodeficiency disorders are conditions in which there is a deficit in the functioning of the immune system, and such deficits can lead to a greatly increased susceptibility of infection in the affected individual, due to these deficiencies of the immune system.

Question 38

What are the two main types of immunodeficiency?

Answer 38

There are two main categories of immunodeficiency disorders, primary immunodeficiencies, mainly genetic conditions in which there are mutations in a particular gene that’s associated with immune functions therefore leading to an inherited deficiency in some aspects of the immune system, and then there are secondary immunodeficiencies where there are acquired defects in immune response that may occur at some point in life.

Question 39

What is an example of primary immunodeficiency?

Answer 39

-A condition called severe combined immunodeficiency, SCID, and there are various types of SCID, but primarily these involve mutations in genes required for development of lymphocytes, so there’s therefore a defect in the development of lymphocytes, and therefore a defect in the generation of adaptive immunity. - So, most individuals born with SCID lack the ability to generate either T or B lymphocytes, so it’s a very severe condition. - It manifests very early in life and babies born with SCID are unlikely to survive the first year of life due to overwhelming infection not treated appropriately. -Sometimes when SCID has been diagnosed, baby has to be kept in sterile bubble to keep them away from any infection causing germs.

Question 40

What is an example of secondary immunodeficiency?

Answer 40

-Best example of a secondary immunodeficiency is acquired immunodeficiency syndrome, AIDS, caused by Human Immunodeficiency Virus, HIV. -HIV specifically infects T helper lymphocytes, because on the surface of T helper cells, there is a particular protein molecule called CD4, and this is the main receptor on surface of cells that HIV can bind to, so it specifically infects T helper cells, and then by gradually depleting body’s T helper cells, individuals lose their ability to generate effective adaptive immunity because T helper cells are required for adaptive immune responses. - If untreated, this destruction of T helper cells, leads to an increased susceptibility of a whole host of infections, and then the HIV infection progresses to clinical AIDS.