Archive for the ‘immunology’ Category
revisiting bronchiectasis
A couple of days ago I had a minor operation on what the specialist (pulmonologist) described as a partially collapsed lung, which sounded rather serious. It certainly impressed others when I mentioned it. I was diagnosed with bronchiectasis more than a decade ago, and I wrote about it at the time, but I can’t be bothered looking it up so I’ll start again.
Bronchiectasis is – at least I thought it was – a kind of damage to the walls of the many tiny airways in the lungs. Those airways become loose and distended, creating cul-de-sacs which collect bacteria. Think of it as a kind of bend in a creek which collects stagnant, smelly water. Not flushing properly. So the affected part of the lung carries a high bacterial load which means a lot of sputum is produced and the victim tends to have a lot of bacterial infections. I also cough a lot, especially in the mornings.
But – and this I think is new to me – bronchiectasis is also an auto-immune disease – and there’s apparently an effective treatment in the offing. I had an interview with the pulmonologist a few days before my op, and he told me he’d just come back from a conference in Tokyo, as you do, at which this treatment was touted. He didn’t go into detail, so I looked it up.
Pulmonary macrophages, neutrophils and Brinsupri, the trademark name for brensocatib, the first ever FDA approved treatment (in August 2025) for non-cystic fibrosis bronchiectasis (NCFBE)…
A PubMed article published in September has this to say in its abstract:
Bronchiectasis is a chronic airway disease marked by irreversible bronchial dilation, persistent cough, and recurrent infections. Its pathogenesis is explained by the “vicious cycle hypothesis,” which involves impaired mucociliary clearance, neutrophil activation, and tissue damage from neutrophil serine proteinases (NSPs). In August 2025, the FDA approved Brensocatib, a selective dipeptidyl peptidase-1 (DPP-1) inhibitor, as the first disease-modifying therapy for bronchiectasis. By blocking NSP activation, Brensocatib reduces inflammation and exacerbation. WILLOW and ASPEN trials demonstrated significant improvements in exacerbation rates, lung function decline, and exacerbation-free survival, establishing a novel therapeutic paradigm for this previously undertreated condition.
So bronchiectasis is an auto-immune disease, in which the over-active production of neutrophils, the most common type of white blood cells, causes ‘unnecessary’ inflammation – or more specifically, the overproduction of NSPs by those neutrophils.
So how to write about this without getting too technical and confusing myself? So there’s clearly a type of bronchiectasis associated with cystic fibrosis, which I’m tempted to explore, but maybe another time. For the rest I’ll obviously be relying on professional sources, referenced below. My type of bronchiectasis is characterised by ‘permanent airway damage, mucus build-up, and frequent chest infections’. This new medication ‘targets one of the causes of inflammation in bronchiectasis, rather than just treating the symptoms’. It inhibits DPP1 (dipeptidyl peptidase 1), an enzyme, or protein, which activates these NSPs – sometimes too much. Over-activity damages lung tissue. So the blocking of this enzyme reduces the inflammation and the damage.
So an obviously interesting question for me is – why do some people get this over-active response by the DPP1 enzymes? Well, here’s what AINL (artificial intelligence never lies) says on this very topic:
An “over-active response” by Dipeptidyl Peptidase 1 (DPP1) enzymes is not typically a result of the enzyme itself being overactive, but rather a reflection of underlyingchronic inflammatory diseases that lead to excessive neutrophil activity and the release of mature, active DPP1. The enzyme itself is often present in high amounts in the sputum and airways of affected patients, correlating with disease severity.
References
https://pubmed.ncbi.nlm.nih.gov/41180673/
Brensocatib: Is this breakthrough a Game-Changer for Bronchiectasis?
https://emedicine.medscape.com/article/296961-treatment#aw2aab6b6b1aa?form=fpf
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immunology – an ongoing fascination
Immunology is one of those strange subjects – those who know virtually nothing about it tend to pontificate about it (I’ve experienced this), while those well-versed in it feel overwhelmed by the complexity of the human immune system and how much they still have to learn, and how each new uncovering opens up more layers of complexity.
I’ve just started to listen to The immunology podcast, some of which sounds to me as if it’s spoken in Yiddish, but it’s not the fault of the presenters – the podcast is clearly aimed at established immunologists and advanced students, with lots of in-house terminology and an assumption of knowledge not yet, and mostly never, possessed by myself. Today I was listening to episode 103 – the most recent – but it was only marginally less comprehensible than episode one (no, I haven’t listened to all the podcasts in between!). It didn’t help that I was walking through Adelaide’s pleasant parklands while listening – lots of lovely avian antics to distract me.
Anyway, let me look at more terms and concepts. Cytokines are small proteins, and there are many types, some of which are slightly familiar to me – interferons, interleukins, lymphokines, chemokines and tumour necrosis factors. Tumour necrosis means the death of tumour cells – which sounds good but often isn’t. Necrosis shouldn’t be confused with apoptosis, which is programmed cell death. More about that later, perhaps. Tumour necrosis factor (TNF) is produced mostly by ‘active’ macrophages. So what’s an active macrophage? AI tells me (I’ve been warned against using AI as a definitive source, but as a starting point it’s generally reliable) that there are two types – classically activated (M1) and alternatively activated (M2). You can see how all these bifurcations complexify the complexities, but let’s stick for now with M1, which are more clearly involved in immunity. AI again provides some basic detail:
They exhibit enhanced phagocytic capabilities, meaning they are better at engulfing and destroying microbes, and they release pro-inflammatory cytokines to recruit other immune cells to the site of infection.
So phagocytes are engulfers and destroyers of pathogens, and macrophages are BIG ones, apparently. So, clearly, anything with the -kine suffix is a small protein involved in the immune system, but not all such proteins use that suffix. Let’s look at interleukins (he said, sounding like a teacher). They’re mostly produced by white blood cells, aka leukocytes, and they act as messengers or signallers between cells involved in the immune system. It’s now known that they’re produced by many types of cells. They’re identified by numbers – IL-1, IL-6, IL-10 etc. Something I worked out today in the parklands!
But just on language, a subject I’m a little more comfortable with, the term cytokine seems to be an amalgam. Kine is a biblical term, though perhaps from later translations, referring to cattle. Perhaps the emphasis, above all, is on plurality. Cyto- is used in the term cytoplasm, and probably refers to something ‘inside’ (AI calls it anything intracellular, and it also explains ‘kine’ in terms of movement – kinesis, kinetic energy, from the Greek).
I very much remember the ‘cytokine storm’ described during the COVID-19 days, which seemed to suggest that people were being compromised, sometimes fatally, by the immune system’s reaction to the pathogen. Cytokine release syndrome (CRS) refers to this, but it can also be a response to immunotherapy. The fever that it may induce can raise a number of unforeseen problems. According to one PubMed article,
A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death.
It’s this kind of reaction that anti-vaxxers use to accuse immunologists of criminality. No doubt they’d interpret ‘deregulated immune system’ as a ‘deregulated immunology system’. But the science can point to huge successes, first with smallpox, and then with so many other potential killers – cholera, tuberculosis, polio, tetanus, diphtheria, whooping cough and influenza, to name a few.
So the same PubMed article, which focuses on COVID-19, lists a number of pro-inflammatory cytokines found in patients with the infection, such as IL-1, IL-2, IL-6, TNF-α, IFN-γ, IP-10, GM-CSF, MCP-1, and IL-10 – IL meaning interleukin, TNF-α meaning tumour necrosis factor-alpha, IFN-γ being interferon-gamma, a type II interferon, IP-10 (interferon gamma-induced protein 10) being a chemokine or small protein involved in many immunological processes, signalling in particular, GM-CSF standing for granulocyte-macrophage colony-stimulating factor (of course), and MCP-1 (monocyte-chemoattractant protein), aka CCL2 (C-C motif ligand 2), which is a chemokine that attracts monocytes and other immune cells to sites of inflammation. A monocyte is another type of leukocyte or white blood cell – let’s see, types of leukocyte include granulocytes, monocytes and lymphocytes.
We’re just beginning, which makes me wonder, what’s more complex, our neurological system or our immune system? Probably a meaningless question.
Anyway, let’s get back to interleukins. Our genome produces more than 50 of them, and they’re vital to the effective functioning of our immune system. Deficiencies, which are rare, are known to be a factor in auto-immune diseases. Wikipedia provides detailed info on only 15 of them, so presumably there’s still more work to be done on their various functions. Some of the detailed structures and functions that are presumably known to immunologists are more or less incomprehensible to me, e.g 12-stranded beta sheet structures. To give an example, of knowledge and manipulation that’s beyond my ken:
Molecular cloning of the Interleukin 1 Beta converting enzyme is generated by the proteolytic cleavage of an inactive precursor molecule. A complementary DNA encoding protease that carries out this cleavage has been cloned. Recombinant expression enables cells to process precursor Interleukin 1 Beta to the mature form of the enzyme.
Right. There’s a mnemonic for some of the ‘important’ interleukins which might be useful, but I won’t give it here (I don’t find it useful). IL-1 is associated with fever and heat, Il-2 is a signalling molecule in T cells, affecting their growth, differentiation and function, and is important in anti-tumour cancer responses, and Il-3 is another signalling molecule, produced by T and other immune cells, influencing macrophages, mast cells (white blood cells which produce histamine and protect against various pathogens and toxins), and the odd megakaryocyte.
Megakaryocytes are, rather obviously, large. They’re present in bone marrow, where they produce platelets – colourless cell fragments important for blood clotting. Platelets circulate in the bloodstream and aggregate at injury sites. They’re also known as thrombocytes. Much of this blog piece will be like a glossary. For example, stem cells. Think of a stem that subdivides into many different parts. They can also simply divide into more of themselves. But a megakaryocyte isn’t a stem cell. Megakaryocytes are more specialised, and are derived from hematopoietic stem cells (HSCs). They arrive at being megakaryocytes ‘through a hierarchical series of progenitor cells’. I’m relying on AI for much of this. So, a HSC is a multipotent stem cell which can differentiate into all the blood cell types. So maybe I’m going beyond immunology here into the whole of biochemistry, but it’s virtually impossible to draw strict boundaries.
Anyway, I shall stop here, or pause, having loaded myself with enough preliminary information. It’s marvellous stuff, and I’ll be going on about it for quite a while….
References
https://en.wikipedia.org/wiki/Interleukin
the immune system 1: introducing the adaptive immune system – MIT lecture
Just something to start with…
It was in 1796 that Edward Jenner created the first vaccine, using material from a cowpox sore on a milkmaid’s hand and injecting it under the skin of an eight-year-old boy. I’ve not been able to ascertain whether Jenner injected the material directly into the boy’s bloodstream. In any case this has been regarded as the world’s first vaccination, a term coined by Jenner (from vacca, Latin for cow). Variolation, using smallpox scabs inhaled by the patient, had been practised in Asia for centuries before Jenner, and was promoted in Britain by Mary Wortley Monagu earlier in the 18th century. Variolation was certainly effective, and for some time there was a dispute about the best treatment. In any case, what was being brought into action by both treatments was the adaptive immune system.
So now to MIT’s introduction to immunology course, presented by Adam Martin. He mentions, in his first lecture, that there are many levels of immunity, and goes on to describe two, innate and adaptive immunity. Innate immunity is ‘the first line of defence’, and acts immediately. Neutrophils, which are white blood cells, are part of this innate system, which is quite static and unchanging, involving a constant surveillance. Adaptive immunity is also known as acquired immunity – and its acquisition takes time.
The adaptive immune system is more specific than the innate. That’s why we need regular flu vaccinations, because flu viruses can evolve quite rapidly. These vaccinations are designed to combat or provide immunity to new strains of the virus.
There are two branches of adaptive immunity: humoral immunity, which is protein-mediated (the proteins are called antibodies). This type of immunity is called humoral because these antibodies are secreted into bodily fluids or humors (blood, mostly). The types of cells that produce these proteins, these antibodies (Ab), are called B cells, which are matured in the bone marrow. The other branch is cell-mediated immunity, which involves T cells, which are matured in the thymus gland, near the top of the lungs.
So far so simple, but next we’re shown a scarily complex chart showing the derivation of all these cells from hematopoietic stem cells – most of these cells comprising the innate system, but also the T and B lymphocytes of the adaptive system (and they’re called lymphocytes because they’re the primary cells found in the lymph). So, it’s important that we can trace the ‘tree’ back to its ‘roots’, the progenitor cells.
Both the humoral and cell-mediated immune system cells have antigen receptors, which recognise specific antigens (Ag). An antigen is any substance that creates/generates an immune response.
Antibodies – goodies; antigens – baddies.
So, the B cell antigen receptor is also called an antibody, and an immunoglobulin (Ig). Structurally, antibodies are proteins with a lipid bilayer, which represents the plasma membrane. Outside of this membrane is the exoplasm, and inside is the cytoplasm. (I’m a little confused here – this sounds like the description of a cell, not a protein). Anyway we’re describing a B cell, and the antibody (protein) can have a trans-membrane domain spanning the plasma membrane, and an exterior Ig domain. These domains are modular folds (polypeptide chains) that are separate from the rest of the protein, and are inserted into the cell membrane, with an N-terminus exterior to the cell and a C terminus within the cell. Each antibody protein has two long polypeptides, the identical ‘heavy chains’ of the molecule. They also have smaller ‘light chains’, and it’s all laterally symmetric. The external tips of these antibodies are what recognises and binds to the antigen.
Now to the T cell receptor (TCR). It’s very different, and simpler, structurally. It has two chains, alpha and beta, and fewer immunoglobulin repeats. The tip of this double chain interacts with the antigen.
The B cell’s receptor, or antibody, has different forms. Some antibodies have transmembrane domains and are anchored in the plasma membrane, but other forms lack the transmembrane domain and instead of being an integral membrane protein, they’re secreted into the blood. The membrane-bound form comes first, but as an infection progresses, the secreted form becomes dominant. The T cell receptor only has the membrane-bound form.
There are many different antibodies, and each given antibody will recognise a different antigenic structure. They can recognise small molecules, proteins, DNA, carbohydrates, lipids, etc. But apparently that’s the B cell’s antibodies. The T cell receptor is more restricted, recognising peptides – short sequences of amino acids – which are presented by the MHC complex (classes 1 and 2). More of that later.
Properties of the immune system. First, specificity – they can finely discriminate between molecules. This is of course essential to avoid the prospect of auto-immune diseases. So, how are such levels of specificity achieved? Well, it’s complex.
Looking at B cell antibodies again, with their heavy and light chains. There are different domains on the heavy chain that are either variable or (more or less) constant. And the same goes for the light chain, with the same lateral symmetry described above. So, looking at the amino acid sequence of the variable part of the antibody (protein) molecule, looking at its structure from N to C terminus …. (?)
By convention, peptide sequences are written N-terminus to C-terminus, left to right (in LTR writing systems) – [from Wikipedia, N-terminus]
Imagine taking these antibodies from the variable region of the chain and aligning them (their amino acid sequence) from N to C. Each is a different antibody (or heavy chain polypeptide) produced by a unique B cell. Then we consider the residue number…
The amino acid residue number refers to the spot in the linear chain where that particular amino acid is found. For example, the number 20 means that amino acid is 20th in the chain.
.. and how much each amino acid residue varies along the sequence. ‘So if we were to align antibody gene stretches like this’, and check out the variation, we could graph it as in the diagram:
The Y axis being the amount of variation, and the X axis is the residue number along the polypeptide sequence. So you see from this graphic that there are three regions of hyper-variability. These regions are also called complementarity-determining regions (CDRs). Apparently there are always three of them?
So what are these regions? We’re shown a crystal structure of one of them (both heavy chain and light chain), with an antigen attached, as well as a ribbon diagram with its CDR, which contacts the antigen. We’re next shown an Ig fold with three loops extending from it, which can bind to external particles. These IG loops vary in amino acid sequence and each tiny variation will affect the binding ability, or affinity to an antigen. So the key here is the CDR.
Each B cell expresses a unique antibody protein, with unique specificity, due to its unique sequence at the CDR region. To get more of a particular antibody, the cell that expresses it can be clonally expanded, creating monoclonal antibodies. Each of those B cells will have an antibody, or antigen receptor, with that same specificity.
So that’s the generation of specificity, but the generation of diversity is also vital for enhancing the immune system. How is this diversity achieved? There are millions of B cells that have unique antibodies, and there aren’t a million genes producing those cells – we have about 30,000 genes. The answer is somatic ‘reshuffling’ or recombination. We have a single heavy chain gene, and two light chain genes, for antibodies. They’re made up of multiple gene segments. Specifically, the parts that make up the variable domain are composed of gene segments that are shuffled during the development of the B cell to give rise to a diversity of proteins.
So we’re next shown a graphic headed, no doubt importantly, ‘the immunoglobulin gene contains multiple V, D and J segments – one of each needs to be brought together to form a functional antibody gene’. The graphic, which I won’t reproduce here, shows the human Ig heavy chain locus on the right. On the left is a variable (V) gene segment, containing 45 variable genes. There’s a diversity (D) segment next to it, containing 23 more of these genes, and then there are 6 joining (J) segments. All of these are distinct regions of the gene, the exon that encodes this variable region of the antibody.
So there are multiple V, D and J segments.To generate a functional antibody, one V has to be brought together with one D, which then has to be brought together with one J to create the heavy chain. So the next graphic has the heading ‘Rearrangement of genomic DNA is needed to put together a gene that encodes an immunglobulin’. It indicates that, for the light chain, only V and J gene segments are required, whereas the heavy chain also requires the D segments. Most of the cells in our body, and also in the germline at the earliest stage of development, have this arrangement. But during lymphocyte development a recombination event occurs which brings the two (V and J), or three (V, D and J) gene segments together. So, recombination at the heavy and light chain genes for the antibody.
This is all quite different from the recombination that occurs during meiosis and the formation of the gametes. That recombination occurs between homologous chromosomes, while this type brings together and deletes segments along one chromosome to bring these V and J segments together (intra-chromosomal recombination) to create an antibody protein. It’s called VDJ recombination, and is specific to lymphocytes, because during the development of B and T cells there is an induction of recombinases that mediate this recombination [?] In this case a recombination mediated by ‘recombination-activating genes 1 and 2’, aka RAG1 and RAG2. All this is lymphocyte-specific, and these recombinases mediate this rearrangement, bringing unique V, D and J segments together. The diversity derives from the fact that each segment has a unique sequence, coding for a unique amino acid sequence, and a distinct protein.
But the body derives further diversity from another process. When these segments are shuffled there is imprecision – nucleotides can be added or subtracted (deleted) when these segments are joined. This generates more amino acid diversity, called junctional imprecision. So we have imprecise recombination, leading to the insertion or deletion of nucleotides [the basic structural units of nucleic acids – RNA & DNA – consisting of a nucleoside and a phosphate group]. If there is a multiple of three nucleotides either inserted or deleted, the result is a functional antibody. A multiple of three is required, to avoid a ‘frameshift mutation’, because ‘a cell reads a gene’s code in groups of three bases when making a protein’. That’s the system upon which it operates – if you inserted/deleted a single nucleotide along the line you wouldn’t get a functional protein.
Another important thing – which happens not as a consequence of this recombination process, but of activating the T cell, which is that in addition to these variations, there’s also somatic hypermutation – an elevated mutation rate at the Ig locus, which increases further the diversity of the amino acid at these variable antibody regions. This is also known as affinity maturation, as it increases the affinity of the antibody for its antigen. Note that this is T cell-mediated.
So the immunoglobulin gene is not expressed until this recombination occurs. So this recombination leads to the expression of either the heavy chain or the light chain gene. This is because the enhancer is downstream in the gene, so by vanquishing the intervening sequence you bring the promoter within range of the enhancer, and the gene is expressed. It’s really quite romantic.
Remember though that there are two copies of these genes – paternal and maternal, so there’s another feature of this system – allelic exclusion. A B cell expresses only one antibody, so if both alleles are expressing, that wouldn’t be the case. With allelic exclusion, if you get a recombination event that leads to a functional antibody for one of your inherited copies of the gene, it suppresses recombination on the other allele, so you will only get one heavy chain and one light chain gene expressed per B cell.
So these junctions between V, D and J segments are found in the CDR-3 region, and are responsible for the high level of variability at the CDR or hyper-variable 3 region.
So the last feature to describe is ‘memory’, the ability to recall a previously experienced infectious substance. The immune system needs to be able to do this, and this is the principle behind vaccination. A vaccine will inject an attenuated or inactivated foreign agent into your bloodstream so that the immune system will be alerted to that antigen if/when it turns up in the system later.
Several ways in which this ‘remembering’ manifests itself, comparing a primary infection with a secondary infection, the adaptive immune system has very different responses. The primary response is a little delayed, taking between 5 and 10 days, while the secondary response is generally between 1 and 3 days. The magnitude of the response, the concentration of antibodies that are produced, is larger the second time around. And the antibodies themselves have become ‘better’. This can be shown by antibody affinity – how tightly the antibody recognises (and binds to?) the antigen. Antibody affinity (‘tightness’ of recognition) is measured as the dissociation constant for an antibody to a given antigen. The lower the number, the tighter the binding. For the primary infection the antibody affinity is weaker, on the order of 10 to the seventh molar in terms of KD [KD, or KD, is a quantitative measure of antibody affinity – ‘the equilibrium dissociation constant between the antibody and its antigen’], and the secondary infection generates antibodies that are functionally better, less than 10 to the negative eleventh molar (sub-nanomolar), a very tight interaction between two molecules. So, more and better. So from the first infection to the next, a type of B cell – a memory B cell – will express an antibody specific to the previously experienced antigen, because, due to irreversible recombination, this will be encoded in the genome. The memory results from VDJ recombination being irreversible, so those memory B cells will be there even if the antigen is not. These cells can be generated by vaccination.
So ‘effector functions of antibodies’. They can bind to a foreign substance, interfering with its functionality. Neutralisation, for example, which means preventing the antigen from entering cells. Also phagocytosis, recruiting phagocytes to internalise the antigen (e.g. a bacterium), and recruiting killing cells to kill cells.(natural killer cells).
The lecture ends with a story in the fight against breast cancer, a treatment based on a mouse monoclonal antibody. So, we can use antibodies from other species to generate treatments. One example is herceptin, which can be used as a treatment for HER2-positive breast cancer. It’s based on a mouse antibody which recognises the HER2 growth factor receptor, which is over-expressed in about 30% of human breast cancers. Researchers have engineered a human antibody with the mouse sequence at its complementarity-determining region. So you have a human antibody, which won’t be attacked or removed by the human immune system, but will recognise HER2, and recruit immune cells to HER2 positive cells, neutralising and possibly killing them. This is the possible therapeutic aspect of antibodies, whatever their source.
So ends the first lecture.
References
https://www.abcam.co.jp/primary-antibodies/kd-value-a-quantitive-measurement-of-antibody-affinity
Mary Wortley Montagu and early immunology
Mary Wortley Montagu, aristocrat, writer, poet, traveller and advocate of variolation
The person I live with recently had a women’s lunch in which the Covid pandemic came up for discussion. One of the women, whom I know to be a white South African by origin, and a Christian (all of which may be irrelevant), said ‘Well I didn’t get Covid, because I wasn’t vaccinated’. Apparently everyone present politely ignored this remark, but it was obviously sufficiently egregious for Sarah to mention it to me afterwards.
The only other thing I know about this woman, whom I’ve met a few times, is that she’s very much an advocate for ‘organic’ produce, and so opposed to GMOs, a topic about which I’ve written in the now-distant past, but which has often come up in SGU podcasts, perhaps most recently in episode 1024’s ‘science or fiction’ segment, in which it was pointed out that the US produces and consumes far more GM food than any other nation, even though, typically for such a divided nation, it protests more vehemently that any other country about the whole GM thing.
Anyway, this woman remarked that she (and so presumably everyone else who survived) didn’t get Covid because she wasn’t vaccinated. So, since ‘because’ is clearly a causal word, in basic logic, she is saying that the vaccine caused Covid. That’s to say the pandemic was caused by immunologists and their vaccines. Ergo, immunologists have slaughtered over 7 million people. The virus itself, presumably, doesn’t exist.
It’s hard to know where to begin with such people, but let’s just kindly say that they can’t think straight. In any case, it reminded me of all the efforts I made to understand the virus, its mode of action, the ACE2 receptor, the ‘cytokine storm’ and so forth, much of which I’ve already forgotten.
And yet…
I often come back to the immune system and its incalculable intricacies, because… well, just because. It’s just fascinating. As are our historical attempts to understand it and manipulate it to our benefit.
So I’ve begun to watch a set of lectures on immunology from MIT, delivered in 2018 – just in time to ready all those students for the SARS-CoV-2 outbreak! The first lecture began with the story of Edward Jenner, cowpox and the first vaccination, back in 1796, and I hadn’t made the connection between vaccine and vacca, the Latin word for cow, and of course vache in French. Silly me. But, even more interesting, on recounting this to my closest friend, she reminded me… who was that aristocrat, Lady Mary Whatsername, who was really the first…
So in the interests of feminist fairness and all, here’s her story.
In 1721, Lady Mary Wortley Montagu brought smallpox inoculation to Europe, by asking that her two daughters be inoculated against smallpox as she had observed practice in Turkey.
That’s from the WHO Brief History of Vaccines, referenced below. But as you can see from that site, it didn’t start with Lady Mary. Variolation, from ‘la variole’, a name for smallpox, goes back many centuries, and involves exposing people to ‘mild’ doses of smallpox to confer immunity. I’m not sure of the ‘how’ of that process – apparently one method was blowing old smallpox scabs into people’s noses, causing them to contract a mild form of the disease. I mean, what could go wrong?
In any case, as with Jenner decades later, this was clever thinking about the inducing of immunity, long before anything much was known about our super-complex two-pronged immune system.
So all of this is introductory to another attempt to get my head around that system, via the glorious magic of the internet. Who needs to pay for a university education nowadays? Well, I suppose I’m lucky I got to learn the world’s biggest international language from babyhood.
So I’ll start my dive into the deeps of our extraordinary immune system in my next post.
References
https://www.sgutranscripts.org/wiki/SGU_Episode_1024
Natural selection – how far does it go?
you don’t control this variability
So let me try to understand something completely different, to do with genetics, neurology and selection theory. I’m reading a rather complex, demanding and ambitious book, published back in 1992, by Michael Gazzaniga, called Nature’s Mind, and sub-titled ‘The biological roots of thinking, emotions, sexuality, language and intelligence’. Selection theory gets a regular mention, and I’m assuming what is meant is the Darwinian theory of natural selection. That’s to say, the idea or finding that phenotypic traits that enable individuals in a species to more effectively survive, thrive and reproduce in their particular environment will be ‘naturally selected’ as against other less favourable traits. And so the species will ‘evolve’, that’s to say change, because individuals with the better-adapted traits for a particular environment will out-compete those without those traits and, crucially, pass on those traits to their offspring. Darwin, of course, could only speculate about how those traits were passed down to the next generation, as the whole story of genetic inheritance and DNA wasn’t fully established until well into the 20th century.
Anyway, Gazzaniga seems to be writing about selection theory as some kind of controversial issue, which surprises me and makes me wonder whether I’m reading him right. So let me focus on Chapter 2, ‘The plastic brain and selection theory’, to help my understanding. Here’s the opening sentence:
Although there is little argument that the selection process is at work at both the molecular and the evolutionary levels in whole organisms, there are major questions about whether the brain develops and functions in accordance with the concept of selection.
I don’t understand what Gazzaniga means by these separate ‘molecular’ and ‘evolutionary’ levels. After all, evolution just means change of a certain type – that’s to say, changes in organisms. And organisms are, of course, made up of molecules, coded for by genes. So the organisational structure of the brain, down to the molecular level (or upwards from the molecular level), has everything to do with our genetic inheritance. So what, then, are these major questions? Gazzaniga puts it this way:
…if, as I argue… the majority of our psychological capacities are the result of natural selection, the developing and static adult brain, which houses the neural circuits that enable the human’s high-powered psychological mechanisms to exist, must develop in a surefire, genetically determined way. At the level of behaviour, for example, we want to see whether or not a baby learns to identify a face, or whether there exist in the brain specific circuits enabling facial recognition, circuits laid down by prior genetic forces arrived at through selection pressure.
So, as I conceive it, Gazzaniga is exploring facial recognition (presumably that of other humans, but ‘face’ isn’t of course restricted to humans) in terms of learning and distinguishing, but also in terms of genes and circuitry that have evolved to render such recognition as vitally important. He cites the Nobel Prize-winning immunologist Niels Jerne’s view that selection operates at the cellular level, even though ‘it might look like instruction occurred at a higher level of organisation’. A ‘signal’ of recognition will prompt a response, once described as ‘unconscious’ (but it seems most scientists today dismiss this as a ‘woo’ word), that has been selected for on the most basic, molecular level.
So this takes us into a bit of immunology. Jerne used three analogies, as described by Gazzaniga: first, ‘the immune system is forever changed by the appearance of each new antigen, just as the brain is somehow changed by each new experience’, second, ‘each system – brain and immune system, appears to have a memory: when the same antigen presents itself a second time to an organism, the latter produces more and better antibodies’, and third ‘the experience one organism has developed for its immune system is not transferable to its progeny, just as my skiing ability is not necessarily transferred to my offspring’.
So, to antibodies, and the kappa light chain, which is present in the antibodies of humans and other animals. In all creatures who have these molecules, there is a variable and a constant part of the chain. They’re made up of amino acids, and the constant section is constant for all humans (and presumably for other species), while the variable part varies individually, or ontogenetically.
It seems that Jerne, and Gazzaniga, have taken this as some kind of analogy for the brain, the plasticity of which has both an ontogenetic (individual) and phylogenetic (species-specific) element. That’s to say, there’s a great deal of ontogenetic plasticity within the brain’s overall phylogenetic structure. I’m not sure if I’m getting this right, though. Here’s more from Jerne, comparing the immune system and the central nervous system:
In the immune system, the constant part of the light chain is obviously laid down in the DNA of the zygote, and it is equally clear that there is DNA in the zygote that represents the variable part of the light chain, although, ontogenetically, this DNA may exhibit an immense plasticity.
In the central nervous system, instincts are also obviously encoded in the zygote, most probably in the DNA. But if DNA acts only through transcription into RNA and translation into protein, and if the phenotypic expression of instincts is based on particular arrangements of neuronal synapses, the DNA through RNA and protein must govern the synaptic network in the central nervous system.
Niels Jerne, ‘Antibodies and learning: selection versus instruction’, 1967
So what to make of this ‘magnificent analysis’ (according to Gazzaniga)? You could say that it’s another brick in the deterministic wall, that ontogenetic plasticity, that which makes me different from you, starts with ‘particular arrangement of neuronal synapses’, or the particular sets of proteins that bring about those arrangements, or, before that…
I’m no doubt being influenced right now by some very recent discussions/arguments I’ve had on the subject of determinism, so I’m probably going further than Gazzaniga intended with his thinking. Or not. I shall continue reading the book to see if he comes to any definite determinist conclusions, or if he even touches on such a touchy subject.
References
M Gazzaniga, Nature’s Mind, 1992
on the lymphatic system and its clever cells, mostly
Activation of macrophage or B cell by T helper cell
Jacinta: So we’re focussing now on the lymphatic system, ‘clear water’ remember. A most misleading definition. So there’s this network of vessels, nodes and ducts….
Canto: What’s a node?
Jacinta: It’s a point of connection, or connections. In plants, a node is a point of branching, like with leaves.
Canto: Yeah I knew that. What’s a duct?
Jacinta: Don’t kid kid. It’s like a vessel, only, somehow different. Maybe bigger? Anyway, nodes go with lymph. There are over 500 of these lymph nodes throughout our bodies. The system does a lot of clean-up work, preserving fluid balance. It’s also much implicated in the immune system of course, and it’s involved in other stuff that’s quite hard to summarise, as you know.
Canto: Something from a reliable enough website:
The lymphatic system plays a key role in intestinal function. It assists in transporting fat, fighting infections, and removing excess fluid. Part of the gut membrane in the small intestine contains tiny finger-like protrusions called villi. Each villus contains tiny lymph capillaries, known as lacteals. These absorb fats and fat-soluble vitamins to form a milky white fluid called chyle. This fluid contains lymph and emulsified fats, or free fatty acids. It delivers nutrients indirectly when it reaches the venous blood circulation. Blood capillaries take up other nutrients directly.
Jacinta: Never heard of lacteals. Have heard of chyle, but don’t know much about it. So chyle contains lymph. But what’s lymph?
Canto: It’s a not-so-clear beige-coloured milky fluid containing lots of WBCs, especially lymphocytes, of course, and fatty stuff. Well, actually, that’s not lymph, that’s chyle. Or both… So there’s this lacteal system of the small intestine, capillaries for absorbing fats – well, actually transporting them… but we need to know what bile is, and emulsification, and lipase, and glycerides and esters, and no doubt much much more.
Jacinta: Well we’ve committed ourselves to learning about the immune system and associated processes for some ineffable effing reason, so let’s soldier on.
Canto: Okay, so bile has nothing to do with Trump, at least not in this context. Bile ducts are this network of tubes inside the liver – well actually there are intrahepatic and extrahepatic bile ducts. Bile itself is a fluid made and released by the liver, for breaking fat down into fatty acids. For ‘digesting’ fat, sort of. Not particularly relevant to the immune system, but it’s all interesting en it? And it can cause problems, such as chronic bile reflux. I suspect I’ve experienced bile reflux, though not chronically. I think it’s also called acid reflux, suggesting bile is a kind of acid.
Jacinta: Or maybe not. Here’s another one of those websites that know more than us:
Bile is composed of ingredients designed to digest fat. While it isn’t an acidic formula, it’s harsh on the sensitive linings of your stomach and esophagus. Chronic bile reflux can erode these protective linings, causing painful inflammation and, eventually, tissue damage (esophagitis).
Anyway, I’m not sure how we got from chyle to bile.
Canto: Right, back to chyle and lymph. Have you heard of lymphoedema? That’s a blockage of the lymphatic system, which causes tissue swelling, mostly in the arms and legs but possibly just about everywhere.
Jacinta: Yes, and things fall apart, the centre doesn’t hold. So let’s get back to lymph nodes and the cells they contain. Within lymph nodes there are germinal centres containing a lot of B cells, or B lymphocytes. These have receptors (B cell receptors) on their membranes which are IgD antibodies, all of which have different binding domains, due to genetic recombination, which allows them to deal with differently structured antigens. Once binding occurs, signals are sent to the lymphocyte’s nucleus, resulting in what’s called receptor-mediated endocytosis. The signalling response creates pseudopods and/or clathrins which pull the membrane inside.
Canto: Ok, sorry to be boringly predicable, what are clathrins?
Jacinta: They’re proteins, very ‘clever’ proteins, as so many of them are. They mediate endocytosis, which is essentially the surrounding and cutting off of extracellular material within the cell, creating a vesicle, called an endosome I think, which might be transported to further action sites. So this is happening within the B lymphocyte. We have this B cell receptor bound to a foreign antigen, and chromosome 6 of this cell then can produce a molecule (MHC2) to ‘fit’ the antigen and fuse it to the cell membrane. This has the effect of activating the B cell, carrying an MHC2 antigen-carrying molecule on its surface, and IgD antibodies. Of course I haven’t explained how the clathrins actually carry out this transformation, because I can’t but I believe it’s all been worked out.
Canto: Yes of course, and now our lymphocyte is an antigen-presenting cell. There are three types of such cells – B lymphocytes, macrophages and dendritic cells. However, the lymphocytes still need to proliferate to be effective, and this requires a stimulus. And so enter the macrophages. These have MHC2 molecules on their surface, bound to a specific foreign antigen, and they also have MHC1 surface molecules bound to a self antigen (as do all nucleated cells). The macrophage presents this MHC2 molecule with its antigen to a type of T cell, described as a’naive’ (i.e. non-specific) T helper cell. These helper cells will have, somewhere on their surface, specific protein molecules, called CD4, that ‘fit’ with the MHC2 molecules, and other specific molecules (T cell receptors) that fit with the foreign antigen. Specific TCRs fit with specific antigens. It’s all a matter of geometry, sort of.
Jacinta: These different types of TCRs are a product of genetic recombination, which involves RAG1 and RAG2 genes, and I can only guess that the R stands for recombination… Now these helper cells have CD3 signalling molecules inside (they send signals to the nucleus), and a molecule called CD28 on their surface. The macrophage has a protein, B7, which interacts with the CD28, and this protein interaction, called a co-stimulation reaction, sends a secondary signal to the nucleus – as opposed to the first, primary signal. This is known as co-stimulation.
Canto: So next, the macrophage starts secreting a molecule called interleukin-1, which binds to a specific receptor on the T helper cell, which results in a third signal to the nucleus, and activation of the T cell. The cell’s genes now produce interleukin-2, which can be secreted and will then bind to a receptor, as an ‘autocrine’, resulting in genes secreting another cytocrine, interleukin-4, and then interleukin-5. With all this, the T helper cell moves to another stage, becoming either a T helper 1 cell (stimulated by interleukin 12) or a T helper 2 cell (stimulated by interleukin 4). So, focussing on the T helper 2, it has activated interleukins 2,4 and 5, the latter two of which are especially important, after these cells have started dividing. That’s when those cytokines are produced.
Jacinta: We might be learning something. Now to the proliferation of the B lymphocyte. Interleukin 4 activates the B lymphocyte to start turning on genes for its proliferation – called clonal expansion. And they will have receptors (BCRs) specific to the foreign antigen. They’ll also have MHC2 surface molecules with exposed foreign antigens. They’re now ‘immuno-competent’ cells, and then, through the medium of interleukin 5, they will start differentiating. Some of these new types of cells are called plasma cells, which have a very prominent rough endoplasmic reticulum (RER), others are called memory B cells. Interleukin 5 and 6 stimulate plasma cells to produce and secrete antibodies specific to particular foreign antigens – or, rather, having variable regions that can adapt to and bind to those antigens.
Canto: And these antigens might be on the surface of bacteria, or not as the case may be. If they can bind to all the antigens on the bacterial (or viral) surface they can render it ineffective (neutralisation). Binding to freely circulating antigens can, however, cause problems. Such binding creates a precipitation reaction and this can be deposited in tissue resulting in a type 3 hypersensitivity. Don’t ask.
Jacinta: This is what United Staters call getting into the weeds, maybe. So that’s surely enough for now.
more baffling immune system stuff
1RH2 Recombinant Human Interferon Alpha 2b – evidemment
Jacinta: We’ve been mostly educating ourselves via the NinjaNerd YouTube series on immunology, which seems very comprehensive and yet comprehensible, for beginners, and then going to other websites for details. Now getting back to cluster differentiation (CD), a commonly used immunological term. Here’s a useful definition:
The cluster of differentiation (CD) is a protocol used for the identification and investigation of cell surface molecules present on leukocytes. CD molecules often act as receptors or ligands important to the function of immune cells.
Canto: That’s useful indeed. Each CD – 4 or 8 or 25 – represents a cluster of differentiation. Differentiated from other clusters. So back to T regulatory cells, which would be differentiated into those cells that predominantly have CD4 or CD8 molecules, as well as TCRs. All to help suppress auto-immune diseases in particular.
Jacinta: So we have these T regulatory cells, as well as helper and cytotoxic T cells, all created in the thymus essentially, and then they’re distributed to the lymphoid organs – the lymph node locations include ‘the groin, armpit, behind the ears, back of the head, sides of the neck and under the jaw and chin‘. There’s also the spleen and its sinusoidal capillaries, where T cells form a surrounding layer known as the ‘periarteriolar lymphoid sheath’ (PALS), more commonly known as white pulp. A large number of T regulatory cells however remain in a thymus region known as the thymic (Hassal’s) corpuscles. They’re also distributed throughout the body – the tonsils, the respiratory tract and so on. All originating from the red bone marrow.
Canto: Well I’m still a little confused about the difference between the innate and adaptive immune systems and whether there really is any clear distinction between them (I suspect not). My own distinction so far is that the innate system is quick and not very specific and well-attuned, and the adaptive is – everything else.
Jacinta: Well, a bacterial antigen releases endotoxins which causes a massive release of inflammatory cytokines, got that?
Canto: Not particularly. Get this:
Endotoxins (lipopolysaccharides, LPS) are agents of pathogenicity of Gram-negative bacteria, implicated in the development of Gram-negative shock. Endotoxin reacts with lipopolysaccharide-sensitive cells producing endogenous mediators such as tumour necrosis factor alpha (TNFα).
That was my first stop in trying to find out what endotoxins are. Needless to say, it’s meaningless to me. Though I know that ‘endo’ means ‘from within’ as opposed to ‘exo’… I think.
Jacinta; If you look that up you’ll find it’s horribly complex. Okay the bacteria release toxins which release cytokines in reaction. There are many different kinds of cytokines, including histamines, prostaglandins and leukotrienes. Amongst other things these cytokines will impact smooth muscle cells causing vasodilation, increasing blood flow causing heat and redness. Cytokines will also contract endothelial cells, causing fluid leakage and permeability, affecting pain receptors. Bradykinins are also involved in vasodilation and increased blood flow. All this induces swelling and pain. Broadly, the four signs of inflammation are: swelling, pain, heat and redness. That answers a basic exam question. Joint immobility is a fifth sign in some extreme cases.
Canto: I’m looking at a different video, “introduction to the immune system”, because I think we need to stay on the ground floor for a while. I also think looking at language might help. For example, ‘cytokines’ feature heavily, and I was thinking that they were like some kinds of proteins or enzymes, something sub-cellular that could whizz about the body, but then I noticed that white blood cells were called leukocytes, and there were lymphocytes and phagocytes… cells! Like, complex organisms. And ‘kine’, apart from being about cattle, is where our word ‘kind’ came from, as in Kinds of Minds. So ‘cytokines’, methinks, are just the vast array of cells relating to the immune system.
Jacinta: Yes, this is good – a phagocyte is an ‘eating cell’. A lymphocyte is a type of WBC that’s involved in the immune system. T cells are lymphocytes, as are B cells. So, yes, they’re complex, gene-containing thingumies, all of them, and lymphocytes are so called because the lymph system is full of them. But note that ‘cyte’ just means ‘cell’, not necessarily of the white or immune kind.
Canto: So starting again at the beginning, with the innate and adaptive systems. So the innate system is what often causes pains and fevers, that redness and itchiness and raised temperature mentioned before – inflammation. Because of the release of cytokines, as you’ve explained.
Jacinta: Ah but here’s where it becomes confusing and unhelpful. On a website designed, I think, for high school biology students I found this:
Cytokines…. are a broad category of small proteins that are important in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines include interferons, interleukins, lymphokines, and tumor necrosis factor.
So it looks like you were right in the first place. It is confusing though. Interferons are proteins, as are interleukins, and ScienceDirect, which is generally reliable, says this:
Cytokines, chemokines, and lymphokines are multifunctional immunoregulatory proteins secreted by cells of the immune system.
So we’ve both been confused, and maybe looking at language origins might confuse us more. Best just to accept what the biochemists say.
Canto: So, are we starting again, again? Let’s look at some of the cytokine types. Interferons are as mentioned, signalling proteins. But what, exactly, is meant by signalling, and what exactly is a protein? A chain of amino acids, je crois. So, signalling – that’s about sending and receiving and responding to signs of change:
Individual cells often receive many signals simultaneously, and they then integrate the information they receive into a unified action plan. But cells aren’t just targets. They also send out messages to other cells both near and far.
So far, so obvious. These signals are essentially chemical. Even neurotransmission reduces down to the chemical level. But we’ll stick with pathogens and immunity. Receivers of signals are generally called receptors, and immune-system cells often, but not always, have receptors within or sticking out of the cell membrane.
Jacinta: Interferons are so-called because they interfere with viruses and such. We’ve actually been able to create them in the lab since the 80s for treating some cancers:
Interferons are the frontline defenders in your body. A variety of cells, including white blood cells, produce interferons in response to infection and other stimuli, like cancer cells. They initiate signaling cascades by stimulating the infected cells and those nearby to produce cytokines.
Canto: But are they the frontline defenders? And they’re cytokines themselves, as aforementioned. Cytokine seems a pretty broad term.
Jacinta: Our refined or not-so-refined new definition – cytokines are types of stuff created by a variety of cells as an immune response to pathogens. As to interferons, don’t worry about it.
Canto: Too late, I’m worried. Here’s another quote:
More than twenty distinct IFN [interferon] genes and proteins have been identified in animals, including humans. They are typically divided among three classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system.
Should we just devote the rest of our lives to interferons and forget the rest?
Jacinta: Everything’s connected to everything else. And we shouldn’t despair – we’ve learned much about the lymphatic system, for example, that we didn’t know before.
Canto: We didn’t know anything before. But yes I’m encouraged. And getting back to language, lymph is apparently Latin for ‘clear water’, which is a good start for thinking about lymphatic fluid, even if it’s anything but clear.
Jacinta: Like sea or river water I suppose. The more you look… Blame all those pesky microscopes and such. Anyway, one video describes the lymphatic system as having three main functions: 1) returning fluid to the heart: 2) helping large molecules (hormones and lipids) enter the blood: 3) immune surveillance.
Canto: Okay let’s look at all that in a bit more detail next time.
stuff on the immune system 2: T cells, mostly
It’s still early days, but gene-therapy modifications of bone marrow stem cells may be the solution to many haematological malignancies
Peter Doherty, An insider’s plague year
something like…
Canto: So we’re going to try and educate ourselves with the help of all these videos out there on the immune system, with hopefully occasional references to the SARS-Cov2 coronavirus. And we’re not going to reference all these videos and websites because it’s just too time consuming and nobody else is going to read this stuff, it’s just for ourselves, mostly much.
Jacinta So in a vid about T-cell development (and they’re a product of the adaptive immune system) we hear that T-cells are produced in the red bone marrow. Why red?
Canto: Bone marrow comes in 2 types:
Red bone marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow bone marrow is made mostly of fat and contains stem cells that can become cartilage, fat, or bone cells.
Jacinta: So it’s not about red bones. So stem cells are like stems, green shoots that can develop into all sorts of different plants?
Canto: Yes and so you can imagine the potential, if we can induce them to specialise in ways that we want. Homo deus and all that. My brief research tells me that they’re found all around the body, not just the marrow. But it doesn’t tell me how they came into being. And there are apparently different types, as in ‘blood stem cells’. So these particular cells are pushed out into the world via sinusoidal capillaries…
Jacinta: Capillaries are the narrowest of blood vessels, I know that much…
Sinusoid capillaries allow for the exchange of large molecules, even cells. They’re able to do this because they have many larger gaps in their capillary wall, in addition to pores and small gaps. The surrounding basement membrane is also incomplete with openings in many places.
Canto: I must say that the number of high-quality, comprehensive videos on immunology, e.g. on YouTube, is such a boon. The comments say it all, ‘if only I had this info available when I was doing my PhD’ etc etc. So back to T cells. They move, I think as precursor T cells, to the thymus, via those capillaries. The thymus is a small gland near the top of the lungs (in the thoracic cavity) which is an essential component of the lymphatic system, itself a part of our general immune system.
Jacinta: It’s described as a primary lymphoid organ – at last I’m going to find out more about lymph! I hope. So the thymus is where T cells develop, and the red bone marrow, another primary lymphoid organ, is where B cells develop.
Canto: And B cells are a ‘type of white blood cell that makes infection-fighting proteins called antibodies’. Whereas T cells fight infections more directly as well as doing a lot of signalling…
Jacinta: Interesting thing about the thymus – it functions mostly through early childhood and adolescence, after which it atrophies, its tissues becoming fibrous and non-functional. So its role in T cell maturation occurs in our early years.
Canto: The thymus secretes different types of chemokines, or chemotactic agents (thymosin, thymotaxin, thymopoetin and thymic factors) which are somehow able to pull these undeveloped T cells in the right direction. This process is called chemotaxis.
Jacinta: A chemical taxi system, how cute. So we mentioned the two primary lymphoid organs, and there are secondary lymphoid organs – the lymph nodes (found in a number of bodily locations) and the spleen (on your left side, just around the bottom of your rib-cage). Just on chemokines – we’ve heard of cytokines, and the worrisome ‘cytokine storm’ that was oft-mentioned during the Covid period. Chemokines are a subset of these cytokines, which are –
‘an exceptionally large and diverse group of pro- or anti-inflammatory factors that are grouped into families based upon their structural homology or that of their receptors. Chemokines are a group of secreted proteins within the cytokine family whose generic function is to induce cell migration’.
Canto: So now we’re looking at these precursor T cells arriving at the thymus. So the thymus has a heap of thymic, epithelial cells which secrete the above-mentioned chemokines, which stimulate certain genes within the T cells to produce two enzymes (proteins), RAG1 and RAG2 (RAG stands for recombination activating gene – the genes encode the proteins). These are types of recombinase…
Jacinta: Think of genetic recombination, or mixing:
Recombinases are a family of enzymes having functional roles in homologous and site-specific recombination. It’s an event in organisms that involves DNA breakage, strand exchange between homologous segments, and ligation of DNA segments using DNA ligase.
Canto: So in this T cell context the gene ‘shuffling’, as it might be called, produces different protein types to deal with different antigen types. For example they produce T cell receptors (TCRs) designed to recognise and ‘receive’ differently-shaped antigens.
Jacinta: So getting back to those chemokines, they’re inducing other genetic activity to produce CD (cluster differentiation) proteins, of which there are various conformations, such as CD4 and CD8. These proteins form on the outside of the T cells, where they, hopefully, bind to MHC (major histocompatibility complex) proteins on the thymic cells. And of course there’s always more complexity – ‘a human typically expresses six different MHC class I molecules and eight different MHC class II molecules on his or her cells’. For now just think MHC-1 and MHC-2. Recognition of the appropriate MHC molecules by the CD4 and 8 proteins is called ‘positive selection’. If positive selection doesn’t happen the T cells will die (apoptosis).
Canto: The next step, assuming T cell survival, has to do with the previously-mentioned TCRs. The MHC molecules on the thymic cells carry a ‘self peptide’, and just to show how complex and relatively recent our immunological knowledge is, here’s a quote from a Pub-Med abstract from late 2001:
Twenty years ago, antigenic and self peptides presented by MHC molecules were absent from the immunological scene. While foreign peptides could be assayed by immune reactions, self peptides, as elusive and invisible as they were at the time, were bound to have an immunological role. How self peptides are selected and presented by MHC molecules, and how self MHC-peptide complexes are seen or not seen by T cells raised multiple questions particularly related to MHC restriction, alloreactivity, positive and negative selection, the nature of tumor antigens and tolerance.
So, if we could imagine ourselves as upper-class kids who entered university in the late 70s, (instead of working in factories or bludging off the dole as we were doing), none of this would’ve been known to anyone and we could’ve helped make the breakthrough…
Jacinta: Woulda-coulda-shoulda. Back again to those T cell receptors (TCRs), which apparently are not supposed to recognise or connect with the thymic cells’ self or antigenic peptides, as that would lead to auto-immune complications. So they’re ‘designed’ for that purpose, so that they don’t recognise those peptides, and don’t connect with them. This is called negative selection. If for some reason recognition does occur, apoptosis will result. That process occurs by the release of FAS (aka APO-1 or CD95 – don’t ask) from the thymic cell to a receptor in the T cell.
Canto: So, up to this point, if the T cell has come through alive, it’s TCR-positive, CD4 positive and CD8 positive. Its CD4 molecule may interact fortuitously with the thymic cell’s MHC2 (but the CD8 doesn’t interact with MHC1). In that case, there will be gene up-regulation of the cell’s CD4 molecules and down-regulation of CD8. That’s to say, CD4s will increase and CD8s will reduce, and it will present other TCRs. This turns it into a ‘T helper cell’. On the other hand, if the cell’s CD8s connect with the MHC1, there will be up-regulation of CD8, down-regulation of CD4, converting it into a cytotoxic T cell. Some of these helper and cytotoxic T cells can further develop into T regulatory cells, aka T suppressor cells, important for auto-immune disease suppression. This is promoted by molecules such as CD25 and interleukin 2.
Jacinta: Ok that’s enough head-spinning for one post, except perhaps just to say that interleukin 2 is ‘a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity’. And we might find out more about what ‘cluster differentiation’ actually means….
Reference
This almost all comes from one video:
what is this thing called lymph? some more…
Canto: So we learned a lot about lymph recently, but strangely enough, it made us hungry for more. So, it has two functions, circulatory and immunological. I’d like get more detail on both those functions, and in particular I’d like to know more about lymphocytes, what they are, how they’re made and what they do.
Jacinta: Sounds like a plan. So first, lymph in the circulatory system. Here’s what I’ve gleaned from an online video. This system brings oxygen and nutrients to all our bodily tissues, as well as removing waste materials. Ultimately this feeding and removal process occurs in the smallest vessels, the capillaries, which penetrate into tissues and organs. Nutrient-rich blood plasma moves out of capillaries ‘at the arterial end of capillary beds, while tissue fluid containing wastes reabsorbs back in at the venous end’.
Canto: Okay, whoa. First, I have difficulty separating left from right, and east from west, what they call directional dyslexia. I also, in a probably related way, have problems with arteries and veins. One goes into the heart, the other goes out….
Jacinta: Haha, think arteries away (AA), and that’s all you need to know. I have the same problem, quelle surprise!
Canto: So I get that nutrient-rich ‘blood plasma’, presumably some kind of mixture of blood and plasma, moves out of arterial capillaries into tissues, to feed and energise and rejuvenate them and such, but I’ve never heard of capillary beds, and ’tissue fluid’ sounds a bit questionable…
Jacinta: These are all good issues to raise. Apparently there’s a whole capillary bed network. So, getting back to basics, our cardiovascular system is this super-complex network of veins, arteries and capillaries that move oxygen, nutrients, hormones and waste materials to and from our tissues and organs. It’s often analogised as something like a city road network, highways with off-ramps leading to main roads, side-roads and such. And capillary beds are the network of smaller vessels leading into and out of particular tissues. Anyway here’s a useful definition from a medical website:
Capillaries do not function independently. The capillary bed is an interwoven network of capillaries that supplies an organ. The more metabolically active the cells, the more capillaries required to supply nutrients and carry away waste products. A capillary bed can consist of two types of vessels: true capillaries, which branch mainly from arterioles and provide exchange between cells and the circulation, and vascular shunts, short vessels that directly connect arterioles and venules at opposite ends of the bed, allowing for bypass.
If all of the precapillary sphincters in a capillary bed are closed, blood will flow from the metarteriole directly into a thoroughfare channel and then into the venous circulation, bypassing the capillary bed entirely. This creates what is known as a vascular shunt.
And, since I know you’re wondering:
A metarteriole is a short microvessel in the microcirculation that links arterioles and capillaries. Instead of a continuous tunica media, they have individual smooth muscle cells placed a short distance apart, each forming a precapillary sphincter that encircles the entrance to that capillary bed.
And as for tunica media, I won’t quote, I’ll put it in my own words. Arteries and veins have three-layered linings called tunicae. The tunica media, as the name suggests, is the middle layer between the inner tunica intima and the outer tunica externa. The make-up and structure of this layer (and the others) varies in relation to the size of the artery. For example, there’s a lot more tissue in the layers of the aorta, the body’s largest artery.
Canto: Great, and yes, intrinsically interesting, but let’s return to lymph. So the lymphatic system is a ‘cleaning up’ and drainage system among other things. There are some 700 lymph nodes throughout the body – armpits, groin, throat, and in the intestines where they’re involved in the absorption of fat. A node in this context is a bean-like structure which filters the lymph passing through it. It contains lots of lymphocytes for combating/consuming pathogens. If the system fails to function properly, oedema or lymphoedema results (a swelling or puffiness). As well as these numerous tiny nodes, there’s the spleen, a multifunctional lymphatic organ located on the left side of our bodies next to the stomach. It produces a range of cells including many types of white blood cells such as murderous macrophages and of course lymphocytes. The spleen is divided into a ‘red pulp’ and a smaller ‘white pulp’ section, and I could go into greater detail about T cell zones and B cell zones and the various functions of these cells and their subdivisions.
Jacinta: Yes I think we have a general sense in that the lymphatic system of nodes and spleen improves circulation through removal and replacement, and immunity through renewal of ageing cells and production of lymphocytes and other antibody-type cells. All of this started with our attempt to get a handle on CFS or ME/CFS or CFIDS and its relation to the immune system. It’s been an interesting little journey into an unknown land for us, and my impression is that there’s still a lot to be learned even by researchers steeped in lymph, so to speak.
Canto: Yes, and it’s given us some little background into immunology and the amazing complexity of the animal body…
References
https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/lymphatic-system
https://en.wikipedia.org/wiki/Lymphatic_system
https://en.wikipedia.org/wiki/Metarteriole
catching up on SARS-CoV-2
Canto: So, having largely ignored COVID-19 in the last few months, since having my fourth vaccine, which came before or after having tested positive (a RAT test) for the virus, with minimal symptoms – and I suppose it may have been a false positive – I hear that it’s still causing serious problems two years on. And I’m still encountering people who make light of the virus, and are ‘on the fence’ about ‘the whole vaccine thing’, so I think we should explore the situation anew – variants, comorbidities, actions to be taken, long covid etc etc.
Jacinta: Okay, another interminable conversation perhaps. Where do we start? According to a graph (see below) on the situation in South Australia, case numbers have spiked a few times in the last year, but the graphic gives no indication of severity of symptoms. The reporting on new cases seems to be more sporadic at the moment, which explains the gap between the lines, which are getting disturbingly longer. We’ve noticed of course, that mask-wearing and other precaution-taking has slackened off during the year, and government-enforced mandates were lifted months ago….
Canto: And few people seem to be concerned about crowded settings any more… The ABC has a state-by state report, referenced below, which gives weekly stats. It shows that in every single state and territory the case numbers for the last week were higher than those of the week before. Their site presents a rather alarming graphic of case numbers over the last four months, which speaks for itself:
Jacinta: And yet, as you say, covid fatigue, or rather covid restrictions fatigue, has set in, and governments are no doubt reluctant to get tough again, unless things get even worse. What I’m hearing, from people much younger than me, is that it’s no big deal for the young and healthy, only elderly people or those with comorbidities need to worry – and of course it’s all a bit overblown. I hesitate to ask if they’ve been fully vaxed – they’ve obviously never heard of Typhoid Mary.
Canto: And that was 100 years ago – the germ theory of disease wasn’t fully accepted then, but now information is easily available.
Jacinta: And so is misinformation. Anyway, the ‘fourth wave’ is now underway, according to the media. According to Dr Nancy Baxter in an ABC interview, our vaccine immunity has declined over time and most covid restrictions are gone, so numbers are increasing again, and hospitalisations are rising.
Canto: My sympathies go to all the medicos, nurses and other such workers out there. What about death rates – and what about variants, where are we with those?
Jacinta: So just over a month ago the federal government’s Chief Medical Officer made this public statement:
We are seeing an increase in COVID-19 case numbers in Australia, reflecting community transmission of the Omicron variant XBB. We are also closely monitoring the overseas transmission of a second Omicron variant – BQ.1. While evidence is still emerging, the experience to date with these two variants overseas is that they do not appear to pose a greater risk of severe illness and death – and that the COVID-19 vaccines provide good protection against these outcomes. All indications are that this is the start of a new COVID-19 wave in Australia. This was to be expected and will be part of living with COVID-19 into the future. The overseas experience is that these new variants have driven increases in case numbers – and hospitalisations at a rate proportionate to these increases – because of their ability to evade the immunity provided by prior infection and vaccination.
So, not more deadly, but each new variant that comes to our attention does so because it has varied sufficiently to evade the immunity provided by previous infections and the vaccines created to target those earlier forms of the virus. So this could be an ongoing problem, as the CMO says.
Canto: So doesn’t this remind you of the antibiotics dilemma? Rapid reproduction means rapid variation, and we can’t keep up, with antibiotics or vaccines. We’re all doomed!
Jacinta: Well, the panic seems to be over – though panic is the wrong word, to be sure – but case numbers continue to be high, though they appear to go in waves, as every new more successful variant comes along. And death rates, which of course lag case rates and are complicated by comorbidity and age factors, are still higher than we’d like them to be. It’s a weird situation we’re in now, with so many people being in denial or just switched off, perhaps because they’ve made it okay thus far. But of course we’re not doomed – we just need to keep informed about our local area, keep up the vaccines as required, and take precautions as necessary. Remember it’s a largely airborne virus, and it loves crowds of people in enclosed spaces.
Canto: Well we might be keeping up with the vaccines, but are the vaccines keeping up with the variants?
Jacinta: Well this week the CDC in the USA came out with an advisory about updated (bivalent) boosters for adults and children – though the adult one came out on September 2, so not so recent…
Canto: What’s a bivalent booster?
Jacinta: That’s a vaccine that confers immunity to two antigens, such as two versions of a virus, as is presumably the case here. So they’re able to tweak vaccines to cover new variants, methinks. Seems to be a bit of a race between antigens and prophylactics. As to keeping up, an article from the Nature website (referenced below) provides reassurance:
Booster shots against current SARS-CoV-2 variants can help the human immune system to fight variants that don’t exist yet. That’s the implication of two new studies analysing how a booster shot or breakthrough infection affects antibody-producing cells: some of these cells evolve over time to exclusively create new antibodies that target new strains, whereas others produce antibodies against both new and old strains.
Canto: So the message clearly seems to be to keep up the boosters, which I strongly suspect young healthy people aren’t doing, so they’re playing dice with their own health as well as threatening the health of others inadvertently, as more of less healthy carriers of the virus.
Jacinta: Yes, it’s really a difficult message to get through to the young, especially if they’re not in contact with serious sufferers or the mortality of loved ones.
Canto: Okay, so it’s an ongoing drama at present. I’m hoping that we can look at the long covid issue sometime soon, another complex problem, due to symptom variety, skepticism, and the whole issue of treatment.
Jacinta: Yes – whether the pandemic is over or not is a live issue. Sometimes I get the impression that it’s over just because people want it to be over. They want to return to ‘normality’ whatever the consequences. The virus may teach us otherwise. We need to keep an eye on it.
References
https://www.health.gov.au/news/new-covid-19-variant-leads-to-increase-in-cases
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bivalent-vaccine