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
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