Chemotaxis

To understand the general principles involved in inflammation, it is not necessary to consider chemotaxis in detail. Chemotaxis is, however, a process which will be of increasing importance to us. Since a detailed consideration of chemotaxis is not necessary for an explanation of inflammation, I have chosen to treat it under its own, distinct heading. It may be preferable for some of you to come back to this after finishing the the discussion of inflammation. Nevertheless, understanding chemotaxis will be important and it is convenient to treat it here, so as to give the fullest explanation of inflammation.

In the case of neutrophils (to take an example), chemotaxis is achieved by the formation of pseudopods. These are temporary extensions of the cell, which roughly resemble feet. When a cell such as a neutrophil detects a concentration gradient of a chemotactic factor, it will physically stretch towards it. That is to say that, where there exists a high concentration of chemotactic factors, the cell will project pseudopods towards that concentration. In this way, the cell directs its movement along the concentration gradient. Pseudopods may be extended and contracted such that they can accurately follow the concentration gradient and respond to any changes. Some examples of these chemotactic factors which are followed by neutrophils are interleukin-8 (IL-8), complement component 5a (C5a), N-Formylmethionine leucyl-phenylalanine (fMLP) and leukotriene B4.

At this point, I am afraid that I'm going to have to become rather vague, because the mechanism by which these pseudopods are created is not fully understood. Nevertheless, we know that the formation of these pseudopods is effected by receptors on the surface of the cell. These receptors are specialised proteins, which bind with the relevant chemotactic factor for that cell. It is believed that this leads to the creation of a gradient of PIP₃ within the cell.

PIP₃ is a phospholipid whose full, unabbreviated name is phosphatidylinositol (3,4,5)-triphosphate and it looks like this:

Figure 1.1: The structural formula of PIP₃. (Image courtesy of "Louisajb," via Wikipedia)

When a chemotactic factor binds to a cell surface receptor, the reaction will bring about a conformational change in the receptor. The receptor will change its shape. In the case of neutrophils, this change leads to the production of PIP₃, which is, naturally, concentrated around the receptor. PIP₃ is involved in a signalling pathway, which is where a series of chemical reactions - beginning with a ligand (literally any chemical which binds to another to form a more complex chemical) binding to a receptor - form the required components to produce a desired effect within the cell. For more information and a detailed example see cell signalling. Suffice it to say, for the time being, that the signalling pathway ultimately leads to the polymerisation of actin filaments. Actin is a protein which is used to build the pseudopods. The external concentration gradient sets up an internal PIP₃ gradient (for PIP₃ will be produced at the site of the receptors, with more PIP₃ produced where there is more of the chemotactic factor to instigate its production) which leads to heightened levels of actin filament polymerisation at that location. These actin polymers connect with the membrane of the cell forming a growth - the pseudopod. Actin filaments can be readily polymerised and depolymerised, allowing for suitably rapid construction and deconstruction of the pseudopods, which allows the neutrophil to follow the concentration gradient.

Inflammation

So, we turn, now, to our first actual process. Being part of the innate immune response, inflammation is not a response to a specific pathogen, but to pathogens in general. It may also result as a response to tissue damage (e.g. as caused by a cut, or a burn) and tissue death; a chemical agent; or, in some cases, one's own cells which are wrongly identified as a threat. Inflammation is characterised by the presence of pain, heat, redness, swelling and, ultimately, dysfunction of the affected area. It has important purposes - even if it can be quite uncomfortable for an individual. The role of inflammation is, ultimately, to destroy any pathogens or other potentially harmful foreign bodies. It does this by containing whatever initiated the response and "recruiting" resources and immunocompetent cells to destroy it. It also serves to remove any tissue which may have been damaged - this allows the affected area to heal effectively.

We will see how this is achieved presently; but it is important to point out that chronic or excessive inflammation can result in very serious problems; this is because the inflammatory response - while helpful - initiates events which can be harmful to health if they are prolonged, or excessive. This can result in, for example, tissue damage and can result from a failure of the regulatory mechanisms of the inflammatory response, or an inability to remove the initiator of the response. Other problems which can result from inflammation include allergic reactions and anaphylaxis. Allergic reactions occur when a harmless agent, such as dust, pollen, or rubber, is misidentified as a threat. An excessive response can result which, if uncontained and systemic - anaphylaxis - can cause serious harm. Even without anaphylaxis, allergies can still be disruptive, for obvious reasons. An individual may need to avoid certain foods, or materials, which can be difficult and affect everyday life. The inflammatory response is also involved in autoimmune disorders - where normal cells of the body are perceived as pathogens and are attacked. Apart from the damage to the cells themselves, this can result in chronic inflammation (for the inflammatory response cannot effectively destroy all of these cells - a good thing) and this is the case with a number of debilitating diseases, such as rheumatoid arthritis. Inflammation caused by substances which can't be removed, such as wood, metal and asbestos fibres, can also progress to chronic inflammation, as we've already seen. Since the foreign body cannot be removed, the inflammatory response is not halted.

How, then, does the inflammatory response work and what, in fact, does it do? Vasodilation (enlarging of the blood vessels) in the local area is one of the first responses. This increases blood flow through the region and is the cause of the redness and the heat. The blood flow increases because the same amount of blood is being pushed (by the heart) through a wider blood vessel, so there is less resistance to the flow of blood. If you pour water out of a bottle and into a cup, you will notice that if you then pour that water out of the cup, the cup will empty much faster. This is because the opening at the top of the cup is much wider than the opening at the top of the bottle. It's the same principle. The increased blood flow increases the presence of cells involved in the immune response, for these are carried in the blood. The walls of the blood vessels (the endothelium) in the affected area also increase in permeability. The cells reorientate to allow important substances such as clotting factors (which impede the spread of the infection) and proteins which can destroy the pathogens (antibodies) to move from the blood vessels into the interstitial fluid - a fluid which surrounds all cells. These substances are transferred through a fluid called exudate and its loss from the blood flow results in a decreased level of blood plasma. As a result, the cells in the blood become more concentrated and the blood more viscous. This then causes a drop in the speed of the blood flow, which causes leukocytes (or white blood cells, which are involved in destroying the pathogen) to drop out of the axial flow. These cells adhere to the endothelium and can pass through it to the site of the infection. This is how the inflammatory response "recruits" the leukocytes. Ordinarily, leukocytes would be retained in the blood flow as shear prevents them from marginating (the name given to this process) along the endothelium. Thus, important proteins are now present in the liquid around damaged cells, wherein also are the pathogens. This allows the process of clearing the infection to begin.

This accumulation of fluid, referred to as oedema, is the cause of swelling often associated with inflammation, and the distortion of tissue caused by the swelling is one of the principle causes of pain. Certain chemicals involved in mediating inflammation - such as bradykinin, which causes vasodilation - also cause the body to experience pain. Serotonin and prostaglandins are other examples. The swellings are also involved in the loss of function which can, in extreme cases, result from the inflammatory response. Function may be lost either due to the pain caused by these swellings, or - simply - due to the swelling inhibiting movement.

Another common aspect of the inflammatory response is fever, which it has been argued may help the activity of the immune system and hinder some pathogens, by increasing body temperature. Fever is brought about by cytokines, which we will look at in more detail shortly, and is another cause of the experience of heat.

Alongside vasodilation and other vascular changes brought about by the inflammatory response, cellular changes are the other key component of the inflammatory response. The response results in the release of chemical signals (chemotactic factors) which can draw cells that attack pathogens to the site of the infection. These chemotactic factors are cytokines - proteins (or peptides, or glycoproteins) which are involved in the regulation of the immune response. Where there is significant tissue damage, vast stores of neutrophils, which are involved in the destruction of cells, are released from bone marrow and drawn to the site of the infection by chemotactic factors. This process is known as chemotaxis and it is not at all simple to understand. Should inflammation persist (usually after 24-28 hours), monocytes will also be drawn to the area of infection. These are cells which develop into macrophages, which destroy pathogens (and, also, dead cells) by digesting them (see Innate immunity). And so it is (partly) that the required cells come to be in the required place and they can then set about dealing with the cause of the inflammation and, ideally, removing it.

Here is where I stop briefly. I will pick up the discussion of inflammation in the post after next (feel free to skip the next post and move straight on to that one). The next post, meanwhile, will be a discussion of chemotaxis. Chemotaxis is very important and it makes sense to talk about it now. It is, though, a separate issue - hence the separate post - and can be read about later.

Innate immunity

As mentioned above, the innate immune system responds in a generic fashion to the presence of pathogens. The simplest and most basic form of the innate immune system is the physical barriers, such as the skin, which I also mentioned above. As we saw there, many of these anatomical barriers are augmented by additional mechanisms, such as the antibacterials present in saliva. It is also noteworthy that many barriers have the ability to expel pathogens by flushing them away, as with tears and sweat. If these barriers are overcome, one of the first responses is inflammation. The other main component of innate immunity is the complement system.

In this section, I will treat both in some detail, but to begin at the beginning, I should like to discuss the cells of the innate immune system. Once we understand what they are and what they do, we can start to think about the processes - like inflammation - in which they participate.

The cells which participate in the innate immune system are types of white blood cell (also referred to as leukocytes). Not all leukocytes participate in the innate immune system, but the ones that do are mast cells, phagocytes, basophils, eosinophils and natural killer cells. (Sometimes γδ T cells are also included, but we don't need to consider them here.) Below, we look at each of these in turn. At this stage in our discussion, I will need to be cursory, but we will be able to look at them in more detail later on, once we have the knowledge to do so.

• Mast cells. Mast cells are located in certain tissues, predominantly connective tissue and mucous membranes. If a mast cell is damaged, or if it detects a pathogen, it releases granules containing histamine and heparin, as well as other molecules involved in regulating and mediating the immune response. Cells which contain granules in their cytoplasm are called granulocytes.
  
  So, to put it very briefly, the mast cell is very much an initiator of the response. Recall, as this is very important, that the innate immune response is non-specific. Should a mast cell be damaged at all, or should it recognise a pathogen, it will always respond in the same way. It will release a number of molecules which effect responses in other cells.


• Phagocytes. A phagocyte is a cell which destroys pathogens (and, also, dead cells) by literally engulfing and digesting them. That is, they "eat" pathogens - hence the name (which is, ultimately, from the Greek phageîn, meaning 'to eat'). This process is referred to as phagocytosis.


• Macrophages. (Abbreviation: MΦ) The macrophage is a type of phagocyte - specifically it is a large phagocyte. Quite simple, really. The role of the macrophage is to phagocytose pathogens and to release a number of enzymes and complement proteins, which mediate the immune response.


• Neutrophils. The neutrophil is also a phagocyte and it also phagocytoses. As well as this, the neutrophil is a granulocyte, releasing - when stimulated to do so - granules of substances (specifically antimicrobials) which serve to destroy some pathogens.


• Dendritic cells. (Abbreviation: DC) The dendritic cells are located in areas such as the skin, which are in frequent contact with the world around us and, therefore, are vulnerable. They also phagocytose pathogens, but they play an important role, too, in the adaptive immune system. We will come to this in due course but, for now, suffice it to say that, having engulfed and digested the pathogen, the dendritic cell then contributes to the activation of cells of the adaptive immune system.


• Basophils. Basophils are another type of granulocyte which release histamine and heparin when they encounter a pathogen.


• Eosinophils. Eosinophils are very similar to basophils. When they encounter a pathogen, they release highly toxic substances which do a good job of dispatching pathogens. Unfortunately, they do quite a lot of damage to the body they're defending, as well. Which is not ideal.


• Natural killer cells. (Abbreviation: NK cells) Natural killer cells are fascinating cells which do not actually attack pathogens themselves, as such. Instead, natural killer cells serve to destroy cells of the body which are damaged in some way. Thus, they can destroy tumours, as well as any cells which are infected by viruses.

These, then, are our cells which are involved in the innate immune response. At the end of this section, I will return to them and give a much more detailed description of these cells and a fuller explanation of how they work.

The Human Immune System

We begin, then, with the immune system. Nature is wonderful - it is truly beautiful - and it is very nice indeed to wax lyrical about it. I, however, am not very good at that and, as this is my work, I'm going to play to my strengths. Nature is full of organisms which exist to reproduce. Life, to borrow slightly from the words of Kahlil Gibran, longs for itself - living things exist to make more of themselves. In order to do this, they need to survive - at least for as long as it takes to successfully reproduce.

Surviving generally requires organisms to make use of other organisms; unfortunately, many organisms do this in destructive ways - the lion preys upon the giraffe, the giraffe feeds on the acacia tree, the Salmonella bacteria infect the human. Not all such uses are destructive, of course - for instance, many plants have a symbiotic relationship with certain animals, in as much as the seeds of those plants are effectively dispersed by the consumption of the fruit. However, many living things are in the business of attacking and harming other living things; perhaps for food, perhaps for a host.

In the spirit of reproduction, defences have evolved against attacks by other organisms. Some of these defences are impressive, dangerous things - like horns. One defence, however, is genuinely much more wondrous. To protect organisms from infection and disease, immune systems have evolved. Some are fairly simple, as in the case of bacteria. The human immune system, however, is a magnificent barrier to infection, disease and - ultimately - death.

As well as protecting organisms against attacks by other living things - such as bacteria - the immune system, of course, protects against pathogens generally, as well. I stress this point because there is debate over whether viruses constitute a form of life. In short, however, the immune system exists to protect living things from infection and disease - caused by infectious agents, many of which are other living things. This is, ultimately, so that living things can reproduce.

One of the most important barriers to infection and the "first defence" - if you like - is the skin. The skin is of vital importance as a mechanical barrier - it serves as something of a wall, physically preventing pathogens - as well as dirt, toxins, poisons and other such undesirable things - from entering the body. This is one reason why severe burns pose such a serious threat. Assuming a patient survives their initial injuries, the loss of skin leaves patients extremely vulnerable to infection, which can cause complications and lead to the death of the patient, who may have been recovering from the burns themselves.

The skin is not the only barrier, however. Complex organisms such as human beings cannot go around sealed in their skin, they need to take materials in and they need to send materials out. Breathing and eating, for example, can potentially significantly compromise the body's defence, which is a little unfortunate. As a result, we have more barriers. The respiratory tract is very sensitive and the reflexes of coughing and sneezing can effectively expel any pathogens that are detected from the body. Unfortunately, as regular travellers on public transport will be aware, this has the effect of spraying them about the place. Furthermore, mucus acts to engulf and trap pathogens - which are then expelled with the mucus - and urine and tears can also flush pathogens from the body. The body also produces a number of antimicrobials and antibacterials. Both the skin and the respiratory tract produce antimicrobial peptides, e.g. β-defensins. Saliva, tears and breast milk contain antibacterials, e.g. the enzyme lysozyme. The human vagina is slightly acidic and the fluids which make it so help to protect against pathogens. Stomach acid, too, destroys many pathogens and - alongside its primary function of digestion - has an important role to play in mitigating the compromising effect of our need to ingest food. It is interesting to note that the presence of flora in the genitourinary and gastrointestinal tracts serves as a barrier against infection as well, as these bacteria provide competition for resources.

Naturally, however, these extensive defences are often breached - partly because humans have a disobliging habit of regularly breathing, eating, copulating and the like. Should pathogens penetrate these defences, other, more destructive elements of the immune system take over. We will look at these in great detail in this chapter; but, before we do so, it is important to distinguish between two categories of immunity:

• Innate immunity. Innate immunity is nonspecific and it is innate - a person is born with it. It is an (evolutionarily) much older, much simpler form of immunity and is also found in plants and simple multicellular organisms.


• Adaptive immunity. Adaptive immunity is much more sophisticated. Developed over time, adaptive immunity confers immunity to specific pathogens and allows for specific responses to specific infections. Furthermore, immunological memory allows for the future recognition of pathogens which have been encountered before, allowing for a faster, more effective response.

Introduction

HIV (Human Immunodeficiency Virus) is - as the name suggests - a virus; more specifically, it is a lentivirus (lentiviruses are a particular genus of retrovirus). This particular lentivirus infects cells of the immune system, which - unfortunately - eventually leads to their destruction, by various means. Over time, with the loss of progressively more cells, the immune system becomes severely debilitated. One important type of cell which is targeted by HIV is the CD4⁺ T cell. When the number of these cells falls below 200 cells per µL of blood, a patient is said to have developed AIDS (Acquired ImmunoDeficiency Syndrome). An alternative criterion for a diagnosis of AIDS is the presence of certain diseases, born of a compromised immune system. With the onset of AIDS, a patient is at an increased risk of opportunistic infection and of developing cancer and, without treatment, their immune system will be unable to respond effectively. Ultimately, this will lead to the premature death of the patient.

HIV is transmitted from person to person through bodily fluids, viz. semen,  pre-ejaculate, vaginal fluid, blood, or breast milk. Approximately 95% of cases diagnosed in the UK in 2010 were the result of sexual activity. Transmission can also occur, inter alia, through the use of a contaminated needle; during childbirth, or when breastfeeding; or through transfusion of the blood of somebody who is HIV positive.

Transmission of HIV can be effectively prevented by practising safe sex, especially through the correct and consistent use of condoms. Pregnant women can also ensure the safety of their child by being tested for HIV during pregnancy. With appropriate medical treatment and, where indicated, birth by Caesarean section, the chances of an HIV positive mother passing the virus onto her baby fall from ≈ 25% to ≈ 2%. Obviously, pregnant women who know they are HIV positive should seek medical advice. Care should also be taken by healthcare professionals and by anybody who uses - or otherwise comes into contact with - needles and syringes. On no account should needles be shared.

Without treatment, the prognosis - according to UNAIDS estimates - is 9-11 years from the initial infection with HIV. Upon developing full-blown AIDS, without treatment, the prognosis is poor - with 6-19 months being the estimated survival time. Adequate medical treatment, particularly the use of high active antiretroviral therapy (HAART), can significantly improve this prognosis. With early detection, a patient can be expected to live for a further 20-50 years; although the prognosis deteriorates the later the treatment is begun.

Because of this, it is very important that HIV/AIDS be well-understood and that HIV positive people be able to get tested and be able to receive the appropriate medical treatment. Sadly, a great deal of ignorance and social stigma continues to surround HIV/AIDS. Many HIV positive people suffer discrimination, fear and violence because of the disease. HIV/AIDS is also surrounded by sham cures, superstition and denialism. The presidency of Thabo Mbeki in South Africa is estimated to have contributed to 330,000-340,000 deaths as a result of AIDS, due to the denialism of that regime. The policy of the Catholic church with respect to condom use is also widely-known: this policy has discouraged (if not prevented) correct condom use, which remains the best protection against the spread of HIV.

I, therefore, intend to present here as thorough an explanation as possible of what HIV is, what it does and how it does it. In order to understand HIV, we must begin by understanding the immune system, which is what HIV affects. Having covered the immune system, we can proceed to examine the virus itself and how it replicates. This will require a thorough knowledge of the cell and of genetics. This will allow us to fully understand HIV and how infection may be treated. This sketch I present here may change somewhat as I go along and I might actually have to have recourse to a certain amount of moving and fiddling and "rejigging." I will of course try, though, to only hit the "Publish" button when I think I've got a finished product worth putting up.

HIV

So, as anybody who's read my little introduction will know, the first thing I shall talk about on this blog is HIV. The first reason for this is presumably fairly obvious - HIV is a truly devastating virus that has ended far too many lives already and affected many times more lives than that. From a much less humanitarian point of view, it is also rather interesting. To understand how HIV works, one needs really to understand what it affects: the immune system - and the immune system is truly fascinating. One also needs to understand a fair bit about genetics and cell biology. So I foresee this blog being broken down into a number of sections, which will probably be like chapters in a book. First I will try to explain how the immune system works and then I will probably need to explain a fair bit about genetics, cell biology and DNA and then we can put the pieces together and understand what HIV actually does and how it works. After the science is over, I will try and say a few things about the very real and very consequential human aspect and might end up talking about what we as humans can actually do.

Now, the disclaimers. I am not a doctor, I am not remotely well-versed in issues such as virology, immunology, epidemiology, genetics or any of the things I'm going to be so presumptuous as to talk about. This isn't just meant as a warning, although it is partly that. Obviously you shouldn't take anything I tell you as gospel, I can't accept responsibility for any harm that befalls you if you do, I cannot guarantee that this blog is nut free, do not try this at home, etc. etc. But as well as that, I am always looking for correction. Feel free not to be unpleasant about correcting me, but I'm a big boy and I can take it if you want to be. But anyway, at the bottom, there is a space for comments. If I get something wrong: tell me and tell anyone else who reads this, too, because I don't want to mislead people. I am writing this as much to learn as to teach, so I may well make mistakes. None will be deliberate and I fully intend that everything I tell you will be accurate and informative, but some of it might not be.

The next thing to say is about my sources, referencing and the like. I intend this blog to have the flavour of something a bit like a textbook. It isn't a textbook by any means, obviously, but I am trying to explain HIV and many of the things I will discuss are "common knowledge" within the fields they belong to. I'm not writing an academic paper, so I hope you will forgive me for not cluttering my paragraphs with little superscript numbers or names of authors in brackets.

But credit must be given where it is due, so at the end of this post I will include a list (which I intend to keep fairly up to date) of all the sources I've found useful. This is my own work, but obviously I didn't discover any of these things for myself, everything I write about I've learned from what other people have written. I am indebted to the material contained in the references I am about to give you and I will be doing nothing more than explaining things which someone else has explained to me. As, I think, with all explanations - and with teaching in general - it's not really possible for me to give a full account of the resources that have helped mold my explanations and my own explanation will be heavily influenced by what I have read. All I can do is acknowledge my debt and try to point you in the direction of some of the most important resources.

References 

Provided below are links to some sites I've found particularly useful and other sources and references. Readers will note that I've made good use of Wikipedia. I think Wikipedia's a fantastic source, but you can decide for yourselves how much you want to trust me, armed with this knowledge. I've tried to put them in some kind of order, but many of these links belong in more than one section. Additionally subsections should not be imagined to be somehow seperate. The links themselves don't really appear in much of an order. I've tried to put more general links at the top in places but really the ordering is essentially chronological.

General information about HIV

http://en.wikipedia.org/wiki/HIV

http://www.tht.org.uk/. This is the website of the Terrence Higgins Trust, an HIV/AIDS charity which also concerns itself with other matters of sexual health. I find them, and their website, to be of substantial value and interest.

"HIV and Me" is a two-part documentary presented by Stephen Fry which first aired on BBC 2. It is available on YouTube, at time of writing. It is a brilliant documentary which is fantastically sad, but really does bring a lot home about the human cost of HIV.

The Immune system

http://en.wikipedia.org/wiki/Immune_system

http://en.wikipedia.org/wiki/Immunological_memory

The innate immune system

http://en.wikipedia.org/wiki/Innate_immunity

http://en.wikipedia.org/wiki/Pattern_recognition_receptor 

http://en.wikipedia.org/wiki/Pathogen-associated_molecular_pattern 

Inflammation

http://en.wikipedia.org/wiki/Inflammation

http://www.britannica.com/EBchecked/topic/287677/inflammation. This is a truly brilliant article containing really everything that matters on the topic of inflammation, all of it explained succinctly and straightforwardly.
http://youtu.be/FXSuEIMrPQk. This is a "Khan Academy" video about inflammation. "Khan Academy" really is a great resource and in some ways an inspiration for me. It is well worth a look.

The complement system

http://en.wikipedia.org/wiki/Complement_system
http://en.wikipedia.org/wiki/Classical_complement_pathway

http://en.wikipedia.org/wiki/Alternative_complement_pathway

http://en.wikipedia.org/wiki/Lectin_pathway

http://biology.stackexchange.com/questions/14278/is-the-complement-system-a-part-of-innate-or-adaptive-immunity. Stack Exchange is a remarkably useful website for asking questions and receiving answers. I also go by the name of "Au101" and you can see the question I asked and the answer I got here.

Mast cells

http://en.wikipedia.org/wiki/Mast_cell
http://www.kegg.jp/kegg-bin/show_pathway?hsa04664
http://wenliang.myweb.uga.edu/mystudy/immunology/ScienceOfImmunology/Hypersensitivitydiseases.html
http://en.wikipedia.org/wiki/FCER1
http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00130/full 

http://etheses.whiterose.ac.uk/2040/2/Sabban,_Sari.pdf

Phagocytes

http://en.wikipedia.org/wiki/Phagocyte
http://en.wikipedia.org/wiki/Phagocytosis
http://www.britannica.com/EBchecked/topic/454919/phagocytosis
http://en.wikipedia.org/wiki/Opsonin
http://www.ncbi.nlm.nih.gov/pubmed/11228151
http://en.wikipedia.org/wiki/Mononuclear_phagocyte_system
http://www.britannica.com/EBchecked/topic/499989/reticuloendothelial-system
http://youtu.be/O1N2rENXq_Y. Another handy "Khan Academy" video.

Macrophages

http://en.wikipedia.org/wiki/Macrophage

Neutrophils

http://en.wikipedia.org/wiki/Neutrophil_granulocyte

Dendritic cells

http://en.wikipedia.org/wiki/Dendritic_cell

Basophils

http://en.wikipedia.org/wiki/Basophil
http://en.wikipedia.org/wiki/Basophil_activation

Eosinophils

http://en.wikipedia.org/wiki/Eosinophil_granulocyte

Natural Killer cells

http://en.wikipedia.org/wiki/Natural_killer_cell
https://mcb.berkeley.edu/labs/raulet/Resources/06-06raulet%20missing%20%23672C34.pdf
http://www.microbelibrary.org/library/immunology/3663-roles-of-natural-killer-nk-cells-in-body-defense
http://bloodjournal.hematologylibrary.org/content/117/8/2297?sso-checked=1

The adaptive immune system

http://en.wikipedia.org/wiki/Adaptive_immune_system 

http://en.wikipedia.org/wiki/Helper_T_cell 

http://en.wikipedia.org/wiki/Antigen_presentation 

http://en.wikipedia.org/wiki/Antibodies

http://biology.stackexchange.com/questions/14172/can-more-than-one-antibody-bind-the-same-antigen

Chemotaxis

http://en.wikipedia.org/wiki/Chemotaxis

http://en.wikipedia.org/wiki/PIP3

http://en.wikipedia.org/wiki/AKT

http://www.bms.ed.ac.uk/research/others/smaciver/Chemotaxis.htm 

http://www.ncbi.nlm.nih.gov/pubmed/12594293

http://en.wikipedia.org/wiki/PI3K

http://www.ncbi.nlm.nih.gov/pubmed/22728827

Cell signalling

http://en.wikipedia.org/wiki/Cell_signalling

http://en.wikipedia.org/wiki/Cytokine 

http://en.wikipedia.org/wiki/NF-%CE%BAB 

http://en.wikipedia.org/wiki/Signal_transduction 

http://en.wikipedia.org/wiki/G-protein-coupled_receptor 

http://en.wikipedia.org/wiki/Toll-like_receptor
http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase
http://en.wikipedia.org/wiki/TLR_1

http://www.cellsignal.com/reference/pathway/Toll_Like.html 

http://www.kegg.jp/pathway/hsa04620 

http://www.ncbi.nlm.nih.gov/biosystems/106390?Sel=geneid:7096#show=genes 

http://www.sciencedirect.com/science/article/pii/S0960982211005975

http://biology.stackexchange.com/questions/15509/how-do-tlr1-tlr2-activate-the-myd88-dependent-pathway

By way of introduction

Okay, before I get into this, I should probably let you all know what I'm hoping to achieve here.

First of all, I blog under the username TUT, which stands for "Tube User's Travels." This refers to my first blog, which was my introduction to the world of blogging. It's how I came to write this one and it's why I'm called TUT - that's why I mention it, but this also serves as a shameless plug. So if you're interested, that blog is here. Over on that blog I essentially talk about my daily commute and anything I notice along the way which I think is worth mentioning. I also use it as an opportunity to talk about my beloved London Underground in general and to explain bits and pieces about its features, its workings and its history. Any other random travels I take are also detailed there. It's quite niche, I must say, and I do go into a lot of minutiae about a network which most people have either never used, or dislike passionately. But I love it and for those who are interested, you can read more there.

That, though, has nothing to do with TUT Talks Science (apart from the TUT part). Over here on this blog, I hope - eventually - to, well, talk science, you'll be amazed to discover. Science has been a real hobby for me certainly since secondary school. I'm gonna take it as read, since you're reading this, that you can understand why. Still, let me just briefly say a few words.

Science is the product of the human mind yearning to discover, yearning to know about the world in which it finds itself, yearning to learn how things work. Or, rather, it is the product of this yearning in many human minds, which collaborate and discuss and share. Science is not really about individuals. There are many big name scientists - Einstein, Newton, Darwin, Feynman, Faraday, etc., etc. Some of then, like Newton, were pretty solitary, unfriendly types by all accounts. Nevertheless, science is not the product of select individuals, but of many and, moreover, whilst many discoveries and ideas come from individuals, many come from groups and teams.

Science, then, is a wonderfully human enterprise and it is the product of humanity. Unfortunately, we know - however - that humans have biases, humans have blind spots, humans can be fooled and tricked by illusions, humans have misconceptions and they have intuitions which apply well only to the world of large, slow moving objects and which break down, for example, when things get very very small and/or very very fast.

Hence, the scientific method, which I hope to talk about in detail. In brief, though, science is based upon evidence. We formulate our ideas on the basis of the facts that we observe and then we go out and test them. We make falsifiable predictions and then we see if we were right. If not, we try again. If so, we invite others to reproduce our results and to critique our work. To aid in this, a number of statistical checks and balances have been developed, as well as a number of useful aphorisms, such as 'correlation does not imply causation.'

So it is - very briefly - that we arrive at "successive approximations of reality," in the words of Ann Druyan. This is very important. In science nothing is sacred, nothing is absolute, unalterable truth, nothing is "known" with absolute certainty. But that does not mean that all ideas are equal, that anything goes. Nor does it mean that anything can be overturned at the drop of a hat. Newton's laws of motion, for instance, are known with a very high degree of certainty. They do not apply at all levels, of course. They are part of classical mechanics. Classical mechanics does not apply to all things, if you want to go down to very very small scales and start talking about the behaviour of electrons, for example, classical mechanics is not very much good. However, Newton's laws, at the scales and speeds we're used to, are not going to be thrown out any time soon.

Science, then, is not just a body of knowledge, it is a means by which knowledge can be acquired, facts can be checked, ideas can be tested and our world can be understood. It is magnificent. Much of this knowledge, of course, can be utilised by clever, enterprising sorts to make life better, to improve our lot. But that's not really what drives science, I think. Not for the theoretical types, anyway. It is, though, nice to think that the knowledge gained is not merely desirable for its own sake - although that would be enough - it can be applied.

All that being said, the knowledge itself is remarkable, it is truly awe-inspiring and it is not, in fact, particularly difficult to grasp. This might seem like an arrogant, self-assured kind of a statement, especially to anyone who considers themselves to be 'no good with numbers,' or who isn't the 'nerdy' sort. I am a nerd, yes, but it is not necessary to be a nerd to understand science. Some science is hard, yes; some science is strange - very strange - it flies in the face of our intuition, it doesn't make sense to us. Some science is built on a considerable corpus of prerequisites. Nevertheless, science can be communicated to those who want to learn. Some of it takes effort, some of it takes time and some of it, whilst it can be summarised in simple terms, cannot be properly treated without the effort and without the mathematics.

But, science can be taught. There is no need to treat people like idiots; if you treat them like idiots, they will respond accordingly, if you tell them they won't understand, they won't. If, however, you take some time and you show them and you teach them, they will learn if they want to learn. There is no need to replace science with cheap, 2 minute articles, full of "fun," slogans, travesties of analogies that do not hold and lazy, uninformed nonsense. The job can be done properly and it should be done properly, because the truth is beautiful. And it matters. It can save lives and it can make living those lives more fun.

That, then, is what I suppose I intend to do. Now, I do not subscribe, particularly, to the "artist" vs. "scientist" dichotomy. Science is my love, a hobby of mine. I - for reasons of my own - chose to pursue a degree in an "arts" subject and I have missed science terribly and I want to get back into it, which is one of the reasons for this blog. But, I think that they are more similar than people realise and I think that human beings are complicated creatures which, by and large, can enjoy both. I am a fairly archetypal nerd, but I still like a bit of the arts and most people are even less firmly on one side of the imagined divide than me.

Nevertheless, I understand that there is a difference. I understand that not all people are scientifically-minded. I am not very good at running, I have no dexterity and no aptitude for physical, sporty pursuits. I see no reason to imagine that such experiences are unique to physical activities, I don't see any reason not to take people who say they're no good with numbers at their word. I don't want to make converts, I've often thought that what the world needs is not more scientists, but better scientists.

So, where am I going with this? Well, my point is, that I don't mind that there are people who'd rather sit down with a good book, than understand how planes fly. That's fine. I, personally, never cease to be amazed that people prefer stories to the truth about our enthralling, captivating world. We know how the leopard got its spots, we don't need to invent stories for ourselves. But, you know what, it doesn't matter, humans have interests and they have talents and they have preferences and that's fine. I can see the appeal of fantasy and fable and story-telling. Few things give me greater pleasure than reading the Harry Potter books, for example.

But...But...Science is interesting. Science is interesting and I really do think that there are things that we know that would delight almost anyone. I don't expect everyone to be interested in science generally, but I think there are stories we have to tell and ideas we have to share that will interest very many. In much the same way that I'm a nerd who enjoys Harry Potter, I very much suspect that there're plenty of dyed-in-the-wool artists who would be fascinated to know how planes fly, for example.

So that is my rallying cry, that is this blog's raison d'être.

Or at least, that's the general idea. As my first foray into all of that, I am turning my attention to HIV. That's my first project and we'll see what happens next, assuming I do get around to finishing it.

So, for the foreseeable future, this blog will form, I hope, a serialisation of my attempt to explain HIV - what it is, what it does and how it does it.