Archive for the ‘immune system’ 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, last encore?…
One way – maybe not a good way – of learning about the immunological system is being alerted to something – a term or an acronym, and going down its rabbit hole to find its connection to things you know a little about. So, neutralising antibodies and Omicron – I’ve taken this phrase from an early episode of The Immunology Podcast (ep 24 – though that wasn’t the main topic of the episode, linked below), Omicron being a late and seemingly less deadly variant of SARS-CoV-2, – what to make of it?
A neutralizing antibody (NAb) is an antibody that is responsible for defending cells from pathogens, which are organisms that cause disease. They are produced naturally by the body as part of its immune response, and their production is triggered by both infections and vaccinations against infections.
Which makes me wonder – aren’t all antibodies neutralising antibodies? Well, there are also binding antibodies, which bind to a pathogen and alert the immune system to its presence so that it can then be destroyed by white blood cells. Neutralising antibodies are a product of B-cells in the bone marrow. They work ‘by affecting how the molecules on the pathogen’s surface can enter cells in the body’. For example, with viruses there are two types, enveloped (they’re inside a lipid membrane) and non-enveloped. The enveloped types are heat-sensitive, the non-enveloped are heat resistant, which sort of makes sense. In the case of the enveloped type, the neutralising antibody blocks its attachment to and entry to the cell, and with the non-enveloped type, the antibody can bind to the capsid protein, which is the protein shell that surrounds the genetic information within a virus cell.
So where do we go from here? Well let’s look at this capsid protein and how the antibody binds to it, presumably to prevent the virus from replicating – what they mean by neutralising? But take this:
Neutralizing antibodies can also stop pathogens from changing their structure and shape, known as conformational changes, in order to enter and replicate within a cell.
So pathogens can change structure and shape once they’re in the body, in order to enter into particular cells within that body? Anyway, there are viruses that can get their way around NAbs by means of regular mutation. Such viruses include Zika and dengue, not to mention influenza. And it can get worse:
A process known as antibody-dependent enhancement (ADE), which leads to more severe infections, can take place when a virus binds to antibodies that help the virus infect cells. The virus is better able to enter into cells in the body and is sometimes more able to replicate once it has entered a host cell.
So it seems these antibodies are a double-edged sword, as these summarising remarks indicate:
Neutralizing antibodies have found application in medicine and are often used as part of vaccines, but they have been found to help viruses enter cells and replicate to cause severe infections, and as such ensuring that neutralizing antibodies will not facilitate infection is an important part of developing vaccines.
So that’s enough of NAbs for now….oh but what about that connection with Omicron? Omicron was/is a highly mutated variant of SARS-CoV-2 which has ‘evolved into many different sub-variants’ according to the abstract of the paper linked below, which lists at least some of these sub-variants, and it’s a long list. It seems these sub-variants may have survived/thrived by being a whole lot less lethal than the original strains. But don’t take my word for it. Anyway the paper was published back in March 2023, and the pandemic was very much on the wane by then I think, so it does seem as if the virus has found an accommodation with our bodies, or antibodies, or whatever.
So enough already, I think it’s time to switch to another topic, I’m way out of my depth with this one. And yet, it’s so…. I’ll keep listening to the podcast, at least.
References
https://pmc.ncbi.nlm.nih.gov/articles/PMC9985919/
https://www.science.org/doi/10.1126/scitranslmed.abn8057
Ep. 24: “Autoimmune Disease” Featuring Dr. Jennifer Gommerman
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
immunity 2: MIT lecture – more on immunity and auto-immunity
So we’re looking at cell-mediated and auto-immunity in this second lecture. We see an image of listeria, an intracellular bacterium, pushing out the edges of the cell, so that it can move between cells without entering the extracellular space. Listeria is a food-borne bacterium which can cause severe intestinal illness. So think of a host cell with an intracellular pathogen, bacterial or viral, taking advantage of these cells to reproduce and spread. This is not good.
B cells, as described before, have an antigen receptor, initially on the plasma membrane, and sometimes secreted into the intracellular space, while T cells only have the membrane-bound form. In any case these antibodies are directed outwardly. How can a listeria-like infection, within the cells, be dealt with? This involves a process called antigen presentation, in which peptides – short sequences of amino acids – are presented and displayed on the cell surface, so that T cells, in this case, can observe what is happening within the cell. This involves another molecule previously mentioned, the major histocompatibility complex (MHC). There are two classes of MHC. Class 1 has a heavy chain – a long polypeptide – and a light chain. So, two polypeptides encoded by different genes. It has two Ig domains proximal to the plasma membrane – and it’s all inserted into this membrane – an integral membrane protein. Then at the other end, distal to the plasma membrane, is another structure, which, looking at its crystal structure, is a ‘beta sheet with two alpha helices’, shaped somewhat like a cup [a beta sheet is a common secondary structure in proteins, formed by polypeptide strands (beta strands) connected laterally by hydrogen bonds, creating a pleated, twisted, sheet-like structure]. Inside the cup is a peptide which displays some of its amino acids, away from the MHC molecule, for T cells to observe.
So these Class 1 MHCs are membrane proteins displayed on all nucleated somatic cells, and the peptides held by these MHCs are derived from the cytoplasm within the cell. They are loaded on to the MHC molecule, which is translated (using ribosomes and types of RNA) on the endoplasmic reticulum (ER), and its extracellular domain is initially present in the lumen (internal space) of the ER. Its peptides come from proteins in the cytoplasm. What happens to these proteins – including unfolded proteins and those that might be ubiquitinated [refers to a protein that has had ubiquitin, a small protein, covalently attached to it, often marking the protein for degradation or influencing its function or localisation – thanks AI, and it has of course dawned on me that this MIT course has followed on from earlier biochemistry learnin] – is that they’re processed by the proteasome [a large, cylindrical protein complex that degrades proteins tagged with ubiquitin, a process essential for maintaining cellular homeostasis and regulating various processes like cell cycle and protein quality control], which this lecturer describes as ‘a kind of shredder-like function for protein’, which cuts the proteins into peptides which can then be pumped into the ER lumen via a transporter, TAP…
The transporter associated with antigen processing (TAP) is a heterodimeric protein complex (TAP1 and TAP2) that transports peptides from the cytosol into the endoplasmic reticulum (ER), where they bind to MHC class I molecules, a crucial step in antigen presentation to cytotoxic T cells.from AI overview
From there they are loaded onto the class 1 MHC molecule. The source of these peptides is from proteins in the cytoplasm, processed by the proteasome. So now that a peptide-MHC complex has been created, it can then be trafficked to the plasma membrane of the cell, where the peptide will be displayed for T cells to observe. The types of T cell that look at these class 1 molecules are known as CD8+ T cells.
There are also class 2 MHC molecules, which have fundamentally different properties. Both molecules display peptides on the cell surface (antigen presentation), but the structure of MHC class 2 is quite different. Instead of a heavy and light chain, there are two chains of roughly equal size, and they’re encoded by different genes than the class 1 MHC. There are two Ig domains proximal to the plasma membrane, and at the end of the MHC molecule there’s a groove or pocket that holds a peptide (aka a peptide-binding cleft).
The class 2 MHC is expressed on a more restricted set of cells. They’re expressed specifically on specialised antigen-presenting cells, such as B cells and phagocytic cells [also known as phagocytes, they are specialised cells of the immune system that engulf and destroy foreign substances, pathogens, and cellular debris through a process called phagocytosis].
Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.
Endocytosis is a cellular process where a cell engulfs extracellular material, forming an internal vesicle to transport substances into the cell. This process, which includes phagocytosis (cell eating) and pinocytosis (cell drinking), is essential for nutrient uptake, cell signalling, and defence against pathogens.
Dendritic cells (DCs) are crucial immune cells that act as sentinels, capturing antigens and presenting them to T cells to initiate adaptive immune responses, effectively bridging innate and adaptive immunity (from AI overview)
References
Immunology 2 – Memory, T cells & Autoimmunity, MIT OpenCourseWare, YouTube video