Lydia.Mx
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Hi! I was wondering if anyone knew why Neutrophils having a multi-lobed nucleus & being twice the size of erythrocytes helps them in their function? I tried to do some research but found little, any help would be much appreciated!
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macpatgh-Sheldon
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Hi,

Very interesting and thought-provoking Qs. We have to apply a little teleological thinking to work out the answers (hitherto unsuccessfully in the case of the first Q - watch this space; I will try and contact one of my ex-classmates at med sch who is a consultant haematologist - this Q will now bug me until I locate the answer! ). One clue I can think of, (applying a principle I often use, which is to check what symptoms a patient complains of when a certain anatomical/histological change occurs in a disease state), is that in megaloblastic anaemia (usually due to folate or vitamin B12 deficiency, in which large, slightly oval erythrocytes (red blood cells) are seen in the blood film), the NEUTROPHILS HAVE HYPERSEGMENTED NUCLEI [see pic below Fig part (c)]- whether this specifically causes any clinical features, I will need to ask my friend; conversely, even more usefully, if there is any (probs extremely rare) disease with lack of segmentation of the neutrophil nucleus, then that would provide even better clues to your Q - again, I shall speak to my friend - watch this space.

2nd Q: the answer, based on conjecture, is that the neutrophil is a large cell because its main function is phagocytosis - the principle is analogous to the fact that a 2 metre long lion [head to tail] weighing 500kg can engulf a whole leg of e.g. a deer more easily than a small dog (of the type lonely old women in UK keep to talk to ) can.

M
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macpatgh-Sheldon
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@Lydia.Mx

Sorry forgot pic!
Name:  Fig 8-8 Abnormal leucocytes.jpg
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Lydia.Mx
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(Original post by macpatgh-Sheldon)
Hi,

Very interesting and thought-provoking Qs. We have to apply a little teleological thinking to work out the answers (hitherto unsuccessfully in the case of the first Q - watch this space; I will try and contact one of my ex-classmates at med sch who is a consultant haematologist - this Q will now bug me until I locate the answer! ). One clue I can think of, (applying a principle I often use, which is to check what symptoms a patient complains of when a certain anatomical/histological change occurs in a disease state), is that in megaloblastic anaemia (usually due to folate or vitamin B12 deficiency, in which large, slightly oval erythrocytes (red blood cells) are seen in the blood film), the NEUTROPHILS HAVE HYPERSEGMENTED NUCLEI [see pic below Fig part (c)]- whether this specifically causes any clinical features, I will need to ask my friend; conversely, even more usefully, if there is any (probs extremely rare) disease with lack of segmentation of the neutrophil nucleus, then that would provide even better clues to your Q - again, I shall speak to my friend - watch this space.

2nd Q: the answer, based on conjecture, is that the neutrophil is a large cell because its main function is phagocytosis - the principle is analogous to the fact that a 2 metre long lion [head to tail] weighing 500kg can engulf a whole leg of e.g. a deer more easily than a small dog (of the type lonely old women in UK keep to talk to ) can.

M
I'm so sorry that I took so long to reply to you, I haven't been on here for a couple of days!
Thank you so much for taking the time to help me and for the such detailed repsonse, I really appreciate it!

Regarding the first question, it is really interesting to think about what you have said & has really helped me to think a bit deeper about what I am learning about - I'm only in my first term of Biology A-level so some of it has gone a bit over my head at this point but I have researched what you were talking about, and although I haven't really been able to come to any conclusions, it has been good to read more synpotically around the subject.
Only thing that I can think of could be maybe to do with increasing the surface area which would help in the efficient engulfment of pathogens or maybe the transport of vitamins throughout the body - as if it has a more flexible, multi-lobed nucleus then this could aid more efficient transport of substances through the tight & narrow capillaries but thats just a complete guess & probably nothing to do with it as it doesn't really relate.
If you do speak to your friend, I would be extremely grateful! Don't worry if not though, I don't want to bother you!

I love the analogy, makes the answer much easier to visualise & it makes much more sense now that I think about it.

Thanks again for the help
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macpatgh-Sheldon
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No probs - Don't apologize for the late reply - what with all this new stuff to digest, and the jump from the baby stuff they teach at GCSE these days (sorry! ) to a bit more thinking at A level, plus the "important" things young girls need to do like visting Superdrug to fill their purses with lipstick and mascara and popping into New Look for one or two (or 50!) leggings/tops, etc., it is a tough life!! (It's OK - only pulling! ).

On a serious note, your way of thinking in trying to work out detail is very good; keep it up! This is precisely the ideal way to approach biology, and if it helps, those were the lines of thinking that came to my mind initially on this Q, although I suppressed those ideas, because a large surface area of the nucleus might aid movement of materials between the nucleus and the cytoplasm, but not between the cell and the outside; your thoughts about the squeezing of cells in tightly fitting capilaries will come in helpful to you when you study about gas exchange in the lungs - the erythrocytes (red blood cells: Greek eryth = red; cytos = container [here cell]) are similar diameter (7 microns) to the diameter of the alveolar capillaries so:-
a) the red cells move slowly, allowing time for O2 exchange.
b) as the endothelium [Greek endo = inside so inner layer, but here the ONLY layer, as capillaries have a wall only ONE CELL thick] is touching the red cell membrane, the distance for O2 to travel is minimized ----> efficient gas exchange.

Keep thinking, thinking, thinking as you are doing! (instead of just learning by rote, as majority of students do) - you will get A* in summer 2020!

Best,
M
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Lydia.Mx
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(Original post by macpatgh-Sheldon)
No probs - Don't apologize for the late reply - what with all this new stuff to digest, and the jump from the baby stuff they teach at GCSE these days (sorry! ) to a bit more thinking at A level, plus the "important" things young girls need to do like visting Superdrug to fill their purses with lipstick and mascara and popping into New Look for one or two (or 50!) leggings/tops, etc., it is a tough life!! (It's OK - only pulling! ).

On a serious note, your way of thinking in trying to work out detail is very good; keep it up! This is precisely the ideal way to approach biology, and if it helps, those were the lines of thinking that came to my mind initially on this Q, although I suppressed those ideas, because a large surface area of the nucleus might aid movement of materials between the nucleus and the cytoplasm, but not between the cell and the outside; your thoughts about the squeezing of cells in tightly fitting capilaries will come in helpful to you when you study about gas exchange in the lungs - the erythrocytes (red blood cells: Greek eryth = red; cytos = container [here cell]) are similar diameter (7 microns) to the diameter of the alveolar capillaries so:-
a) the red cells move slowly, allowing time for O2 exchange.
b) as the endothelium [Greek endo = inside so inner layer, but here the ONLY layer, as capillaries have a wall only ONE CELL thick] is touching the red cell membrane, the distance for O2 to travel is minimized ----> efficient gas exchange.

Keep thinking, thinking, thinking as you are doing! (instead of just learning by rote, as majority of students do) - you will get A* in summer 2020!

Best,
M
Haha this made me laugh, I wish, if only life was that simple!

Thank you! Its good to know that you thought along those lines when you first saw the question because I thought I was just being stupid to be honest. This is really useful - I hadn't thought about that but now looking back, like you said, I can see how that wouldn't apply now. I haven't done gas exchange & am starting it next week so I shall keep this in mind!

Again, thank you so much for your help, you know so much!
Haha - honestly, I'm not sure that will happen but I can hope anyway, thank you.

Lydia
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macpatgh-Sheldon
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Lydia.Mx

Hi Lydia (I month after your last post here - sorry!)

The answer to your 1st Q above is not definitely known, but I have to give VERY STRONG credit to your thinking ability, which appears to have surpassed Sheldon's - there ACTUALLY IS one theory that agrees with your original idea of the reason for a multi-lobed nucleus in neutrophils. It helps them pass through narrow spaces when reaching areas where they are needed for their phagocytic function (WELL DONE! - I have to take my hat off to you , and fling it onto the hat-stand (Sheldon is only one of my nicknames - one other is 007!).

Check out this text copied from the attached research paper! (I WOULD STRESS BEFORE YOU READ IT THAT THIS IS FAR FAR beyond ANYTHING you would need at A level - I am ONLY providing it for to satisfy your curiosity!! - DO NOT WORRY if you do not understand or remember much of it!

ONCE AGAIN BEST OF LUCK next year! - as I said b4, I am happy to answer any other thought-provoking Qs!

Neutrophils

Mammalian neutrophils—and avian or reptilian heterophils (Claver and Quaglia 2009)—have segmented, multi-lobed nuclei, usually containing between two and five lobes, separated by thin filaments of nucleoplasm with little to no internal chromatin. The lobed structure develops from a spherical myelocyte precursor, gradually increasing the number and prominence of lobes through the concave metamyelocyte and band cell stages to the mature neutrophil (Fig. 1b).Chromosome painting and 3D analysis have shown that most chromosomes are randomly distributed within neutrophil lobes, but the organisation can change upon bacterial stimulation (Yerle-Bouissou et al. 2009; Mompart et al. 2013). Within each lobe, the chromatin organisation follows a general gene-density based arrangement, in which the gene-poor chromatin is located towards the nuclear periphery, and gene-dense chromatin more internal (Hübner et al. 2015). Curiously, the inactive X chromosome in women is frequently found in a terminal lobe, often with a distinct ‘drumstick’ appearance (Karni et al. 2001), and it appears that the position of the inactive X within the precursor myelocyte may determine the polarity of the neutrophil. It remains unknown how polarity is determined in XY neutrophils.Hypersegmentation of neutrophils, to six or more lobes, is associated with megaloblastic anaemias, such as result from deficiencies in Vitamin B12 and folic acid, and iron deficiency anaemia (Westerman et al. 1999). It is also associated with Boucher-Neuhäuser syndrome (Umehara et al. 2010; Koh et al. 2015), a lipid metabolic defect. In rats, vitamin A deficiency caused hypersegmentation, linked to a requirement of retinoids for differentiation of promyelocytes to mature neutrophils (Twining et al. 1996). Consequently, there are clearly many pathways that contribute to the establishment of a lobed nuclear morphology. What though is it for?

Functional significance of a lobed nucleus

It is thought that the lobular arrangement makes the nucleus easier to deform and, hence, help the neutrophils pass through small gaps in the endothelium and extracellular matrix more easily (Hoffmann et al. 2007); granulocytes with defects in lamin B receptors (a component of the inner nuclear membrane) are unable to adopt a normal segmented shape, have fewer lobes (Hoffmann et al. 2002), and are poorer at passing through these small spaces. Neutrophils also have a higher variability in the length of the linker DNA between nucleosomes than T-lymphocyte populations (Valouev et al. 2011), pointing to increased chromatin flexibility.However, neutrophils are not the only migratory cell in circulation; circulating monocytes, for example, have a lobed nucleus but, as described below, the lobes are larger and fewer. Monocytes are also flexible enough to enter tissues, whereupon they differentiate into various other cell types including macrophages. Indeed, comparisons of the migration of monocytes and neutrophils suggest that the monocytes are at least equally flexible when penetrating basement membranes, and that neutrophil migration is aided by reorganisation of the extracellular matrix via proteolytic cleavage of laminins (Voisin et al. 2009). The circulating fibrocytes and lymphocytes mentioned below are also migratory and have spindle-shaped and spherical nuclei, respectively.Consequently, while the lobular shape of neutrophils may aid migration, is not strictly necessary for migration. Why then should neutrophils adopt lobes, when other cells do not? Perhaps the answer lies in the lifespan of the cells. The half life of a neutrophil in circulation is about 6 h (Summers et al. 2010). Though circulating monocytes live only a couple of days, macrophages may live for months in a tissue, as can lymphocytes.The granulocytes have lower lamin protein content than macrophages or monocytes—predominantly a loss of the lamins A and C, with an increase in lamin B (Hoffmann et al. 2007). The lamin proteins, as described in more detail later, provide structural support to the nucleus, and protect against damage from mechanical stresses. Particularly, the ratio of lamin A:B balances the stiffness of the nucleus against its elasticity (Shin et al. 2013). Correspondingly, defects in the lamins associated with normal aging affects nuclear shape in all the granulocytes (Scaffidi et al. 2005; Chan et al. 2010), a result of changes to the stiffness and structure of the nuclear lamina. These age-related structural defects are also seen in laminopathies such as Hutchinson-Gilford Progeria Syndrome (Worman and Courvalin 2005).Furthermore, rats treated with cyclophosphamide (a DNA cross-linker that disrupts DNA replication) have hypersegmented tetraploid neutrophils in their blood (Kotelnikov et al. 1988). The underlying mechanism driving hypersegmentation seems to be both failures during DNA synthesis and DNA damage or loss of nuclear structural integrity. Consequently, it appears that the extra flexibility of neutrophil nuclei comes at the cost of lowering their lifespan (Harada et al. 2014), a cost that other, longer-lived cell types cannot bear.
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macpatgh-Sheldon
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Lydia.Mx

For some reason, TSR did not let me upload .pdf, so here's its source!

https://www.ncbi.nlm.nih.gov/pmc/art...rticle_614.pdf

M
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Lydia.Mx
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(Original post by macpatgh-Sheldon)
Lydia.Mx

Hi Lydia (I month after your last post here - sorry!)

The answer to your 1st Q above is not definitely known, but I have to give VERY STRONG credit to your thinking ability, which appears to have surpassed Sheldon's - there ACTUALLY IS one theory that agrees with your original idea of the reason for a multi-lobed nucleus in neutrophils. It helps them pass through narrow spaces when reaching areas where they are needed for their phagocytic function (WELL DONE! - I have to take my hat off to you , and fling it onto the hat-stand (Sheldon is only one of my nicknames - one other is 007!).

Check out this text copied from the attached research paper! (I WOULD STRESS BEFORE YOU READ IT THAT THIS IS FAR FAR beyond ANYTHING you would need at A level - I am ONLY providing it for to satisfy your curiosity!! - DO NOT WORRY if you do not understand or remember much of it!

ONCE AGAIN BEST OF LUCK next year! - as I said b4, I am happy to answer any other thought-provoking Qs!

Neutrophils

Mammalian neutrophils—and avian or reptilian heterophils (Claver and Quaglia 2009)—have segmented, multi-lobed nuclei, usually containing between two and five lobes, separated by thin filaments of nucleoplasm with little to no internal chromatin. The lobed structure develops from a spherical myelocyte precursor, gradually increasing the number and prominence of lobes through the concave metamyelocyte and band cell stages to the mature neutrophil (Fig. 1b).Chromosome painting and 3D analysis have shown that most chromosomes are randomly distributed within neutrophil lobes, but the organisation can change upon bacterial stimulation (Yerle-Bouissou et al. 2009; Mompart et al. 2013). Within each lobe, the chromatin organisation follows a general gene-density based arrangement, in which the gene-poor chromatin is located towards the nuclear periphery, and gene-dense chromatin more internal (Hübner et al. 2015). Curiously, the inactive X chromosome in women is frequently found in a terminal lobe, often with a distinct ‘drumstick’ appearance (Karni et al. 2001), and it appears that the position of the inactive X within the precursor myelocyte may determine the polarity of the neutrophil. It remains unknown how polarity is determined in XY neutrophils.Hypersegmentation of neutrophils, to six or more lobes, is associated with megaloblastic anaemias, such as result from deficiencies in Vitamin B12 and folic acid, and iron deficiency anaemia (Westerman et al. 1999). It is also associated with Boucher-Neuhäuser syndrome (Umehara et al. 2010; Koh et al. 2015), a lipid metabolic defect. In rats, vitamin A deficiency caused hypersegmentation, linked to a requirement of retinoids for differentiation of promyelocytes to mature neutrophils (Twining et al. 1996). Consequently, there are clearly many pathways that contribute to the establishment of a lobed nuclear morphology. What though is it for?

Functional significance of a lobed nucleus

It is thought that the lobular arrangement makes the nucleus easier to deform and, hence, help the neutrophils pass through small gaps in the endothelium and extracellular matrix more easily (Hoffmann et al. 2007); granulocytes with defects in lamin B receptors (a component of the inner nuclear membrane) are unable to adopt a normal segmented shape, have fewer lobes (Hoffmann et al. 2002), and are poorer at passing through these small spaces. Neutrophils also have a higher variability in the length of the linker DNA between nucleosomes than T-lymphocyte populations (Valouev et al. 2011), pointing to increased chromatin flexibility.However, neutrophils are not the only migratory cell in circulation; circulating monocytes, for example, have a lobed nucleus but, as described below, the lobes are larger and fewer. Monocytes are also flexible enough to enter tissues, whereupon they differentiate into various other cell types including macrophages. Indeed, comparisons of the migration of monocytes and neutrophils suggest that the monocytes are at least equally flexible when penetrating basement membranes, and that neutrophil migration is aided by reorganisation of the extracellular matrix via proteolytic cleavage of laminins (Voisin et al. 2009). The circulating fibrocytes and lymphocytes mentioned below are also migratory and have spindle-shaped and spherical nuclei, respectively.Consequently, while the lobular shape of neutrophils may aid migration, is not strictly necessary for migration. Why then should neutrophils adopt lobes, when other cells do not? Perhaps the answer lies in the lifespan of the cells. The half life of a neutrophil in circulation is about 6 h (Summers et al. 2010). Though circulating monocytes live only a couple of days, macrophages may live for months in a tissue, as can lymphocytes.The granulocytes have lower lamin protein content than macrophages or monocytes—predominantly a loss of the lamins A and C, with an increase in lamin B (Hoffmann et al. 2007). The lamin proteins, as described in more detail later, provide structural support to the nucleus, and protect against damage from mechanical stresses. Particularly, the ratio of lamin A:B balances the stiffness of the nucleus against its elasticity (Shin et al. 2013). Correspondingly, defects in the lamins associated with normal aging affects nuclear shape in all the granulocytes (Scaffidi et al. 2005; Chan et al. 2010), a result of changes to the stiffness and structure of the nuclear lamina. These age-related structural defects are also seen in laminopathies such as Hutchinson-Gilford Progeria Syndrome (Worman and Courvalin 2005).Furthermore, rats treated with cyclophosphamide (a DNA cross-linker that disrupts DNA replication) have hypersegmented tetraploid neutrophils in their blood (Kotelnikov et al. 1988). The underlying mechanism driving hypersegmentation seems to be both failures during DNA synthesis and DNA damage or loss of nuclear structural integrity. Consequently, it appears that the extra flexibility of neutrophil nuclei comes at the cost of lowering their lifespan (Harada et al. 2014), a cost that other, longer-lived cell types cannot bear.
Hi, for some reason, I have only just got a notification through, telling me that you've posted on this thread so I'm so sorry!

I really appreciate you taking the time to find this information for me, its been driving me crazy for weeks! Thank you - this is amazing, I will take a read of this later and add that to my notes!
The information does look extremely complicated haha but I like a challenge so we will see what I can take from it.

Thanks again for all your help, you are a life saver!!
You'll probably hear from me again over the next few weeks when I find something else I don't understand haha!!
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