stuff about Covid-19: cytokine problems
Canto: So what are cytokines? They’re ‘signalling proteins, usually less than 80kDa in size’ – that means kilodaltons, and it refers to molecular mass. Proteins have a huge variety of shapes and sizes, the largest being titin, with a mass of 3,816,188.13 Da. I don’t know why they don’t keep to kilodaltons. I presume the daltons measurement is in memory of the pioneering British chemist John Dalton, a truly inspiring character. Cytokines are quite small proteins, I think. Or peptides, which are described on other science sites as not being proteins, or not quite, which is confusing.
Jacinta: We’re looking at a ScienceDirect website which is pretty technical, but it says cytokines regulate many biological functions including those related to innate and acquired immunity. Here’s its ‘operational definition’:
Cytokines can be defined operationally as polypeptides secreted by leukocytes and other cells that act principally on hematopoietic cells, the effects of which include modulation of immune and inflammatory responses.
So peptides are short strings of amino acids, and proteins are longer strings of amino acids, so polypeptides are apparently more than just peptides but not quite proteins. Very weird. Leukocytes are white blood cells, of which there are three main types (I think): monocytes, lymphocytes (T cells and B cells) and granulocytes (neutrophils, eosinophils and basophils). Leukocytes are made in our bone marrow and are found in our blood and lymph. I’d love to learn about lymph one day.
Canto: So leukocytes are part of our immune system, as are the cytokines they secrete. Hematopoietic cells – always worth breaking things down: hema, or haema, always refers to blood, and poiesis, from ancient Greek, essentially means production or bringing into being. Presumably, then, these hematopoietic cells exist in the bone marrow, where they produce leukocytes. And yet… that all seems to mean that cytokines are secreted (and presumably produced) by leukocytes to act on hematopoietic cells that produce leukocytes… It seems a bit circular to me.
Jacinta: Certainly complex. Let’s barge on. The ScienceDirect site has it that cytokines are secreted by many cell types, often at high concentrations, and are mostly involved in cell-to-cell interactions with neighbouring cells. This is called paracrine signalling, as opposed to other forms of signalling (endocrine, juxtacrine and autocrine). However, cytokines can sometimes use those other forms. There are many different groups of cytokines, usually named for their most significant effects, as we see them, but they’re actually pleiotropic, meaning they have each a variety of functions, and those functions can be mediated by other cytokine groups. So, certainly complex, but in terms of their function in response to airways diseases…
Canto: But now I’m hearing that Covid-19 isn’t necessarily an airways disease, or only an airways disease. It may affect the brain and the nervous system, the kidneys, the heart, the blood…
Jacinta: Hmmm, so much more to explore, before we all die. But knowledge is power, the more we know, the more we can defend ourselves. Let’s all be Popperian optimists and rise to the challenge. Here’s an overview, from a 2009 article on cytokines as related to asthma and COPD:
The major classes of cytokines include: pro- and anti-inflammatory cytokines, cytokines of neutrophil and eosinophil recruitment and activation, cytokines derived from T-helper (Th) and T-regulatory (Tregs) cells, and cytokines of T-cell recruitment and growth factors.
The cells mentioned are all leukocytes. But the storm of cytokines may well be causative of those other symptoms found in Covid-19 sufferers, such as blood clots. A very recent article in the Lancet has this to say in reference to what we’re seeing:
the overproduction of early response proinflammatory cytokines (tumour necrosis factor [TNF], IL-6, and IL-1β) results in what has been described as a cytokine storm, leading to an increased risk of vascular hyperpermeability, multiorgan failure, and eventually death when the high cytokine concentrations are unabated over time. Therefore, therapeutic strategies under investigation are targeting the overactive cytokine response with anticytokine therapies or immunomodulators, but this must be balanced with maintaining an adequate inflammatory response for pathogen clearance.
Canto: Wow, I suppose one thing we’ll be learning fast from this pandemic will be a lot more about cytokine production and how it can be abated without risk to the immune system. I wonder if there are any ‘anticytokine therapies’ at present?
Jacinta: Well I’ve read this Lancet article and I can’t pretend to comprehend all that’s in it, but of course it tries to address all we’re concerned about here so I’m going to try to explain it in my way. Hospitalised Covid-19 patients are presenting with pneumonia, ARDS and other respiratory conditions, and sepsis. Sepsis is a broad term, referring to an unbalanced blood immune response which, at its worst, can lead to multiple organ failure. Vascular hyperpermeability, mentioned above, is defined as ‘the excessive leakage of fluid and proteins from blood vessels to the interstitial space‘, being the fluid-filled space around tissue cells. The protease thrombin, which is apparently a coagulant (among other things) and not itself a cytokine, is in normal circumstances tightly regulated in the body by multiple factors, all of which can be impaired by hyperinflammatory conditions. The procoagulant-anticoagulant balance is disrupted, which can lead to microthrombosis and ‘disseminated intravascular coagulation’. Which I think is self-explanatory, and not good. The article refers to ‘raised d-dimer concentrations’ which has to do with fibrin, a fibrous protein involved in blood-clotting. The difficulty is that treatment with ‘endogenous anticoagulants’ has its dangers, shown in previous negative trials. There’s this important factor in respiratory physiology called the ventilation/perfusion (V/Q) ratio, with V being the measure of air getting to the alveoli, and Q the measure of blood getting to the alveoli. A mismatch there can affect the possibility of venous thromboembolism – blood clots, to oversimplify. What this forbiddingly technical Lancet article is suggesting, finally, is that studies conducted on murine [rat/mouse] models of PAR-1 antagonists (PAR-1 being protease-activated receptor, the main thrombin receptor mediating platelet aggregation) have shown some promise, and need to be further investigated tout de suite. Here are the authors’ final words:
Targeting thrombin, coagulation factor Xa or PAR-1, might therefore be an attractive approach to reduce SARS-CoV-2 microthrombosis, lung injury, and associated poor outcomes.
References
https://en.wikipedia.org/wiki/John_Dalton
https://www.sciencedirect.com/topics/neuroscience/cytokines
https://www.medicalnewstoday.com/articles/326701
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/leukocyte
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30216-2/fulltext
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