Red blood cells, RBC's, are normally pretty boring cells that just carry oxygen about. A while back I was wondering what the consequences would be if you could have a liquid that could carry oxygen rather than blood cells, which I thought would make a lot more sense. This I considered to be obvious - if oxygen was freely available, along with glucose, how would you stop bacteria and protists -that like oxygen- from feeding on your fatty acids and glucose, so fervently that they'd do erasily as well as your own phagocytes? That would be disasterous. However, there is a fish with no red blood cells at all, and this is a polar fish.

"The only known vertebrates that don't use erythrocytes for oxygen transport are the ice fishes (family Channichthyidae); they live in very oxygen rich cold water and transport oxygen freely dissolved in their blood.[3]"

http://en.wikipedia.org/wiki/Red_blood_cell

Whether or not oxygen is bound to keep it away from critters such as fungi is an open question. I'd suspect it did play a role, but I also guess that along capilleries microbes could get the oxygen they want from the RBC's. But, if this is so, it would suggest that RBC's had evolved in part for immune system purposes, not just because they are good ways to distribute oxygen in a controlled way and raise the capacity of blood (that they do, but they also raise viscosity, surely, so the blood flow must be reduced). That then led onto this thought - what participation does RBC's have on fighting infections?

I would expect that RBC's are involved in a number of ways and are immunologically vital. For example, they may be able to contain O2 release at sites of infection? It is possible because there is a signalling that occurs between blood vessel cells and RBC's before the oxygen is titrated out - on demand. This indicates that there is a desire to restrict O2 availability except where needed. Most people would explain that as a result of avoiding needless oxidative stress, but I would consider it also likely that it could have a front line immunological function. The blood vessels ought to be able to control their own uptake from their saupply, much like they can with glucose.

Then the wiki came to the rescue with a couple of links. Not quite the kind of immune process I was wondering, but potentially related and very interesting all the same, I'm sure you'll agree:



So, this is similar to what I was saying, except that, it takes it a stage further in elaboration. Not merely is the purpose of oxygen carriers a means to restrict it to microbes, but clearly since it will be avilable to them, it needs to come with a punch all its own to protect us from invasion and attack. And what better punch than to use the oxygen itself?!! This hapopens both in RBC and in liquid carriers as used in crustaceans, and that suggests to me that oxygen has to be made available in a safely controlled way or in a toxic one.

No one had seen this immunological attack by RBC, but we should have, because immune cells use the aerobic power of their metabolic pathways and oxygen to corrode invaders. RBC's are first on the scene in sudden injury and will tend to arrive if infection is bad enough or if immune cells cause sufficient damage.

The Immune Response to Invasion

The immune response is initially triggered by tissue damage and by embedded immune cells, signalling to blood vessels. These in turn dilate, causing fluid to swell up in that area. This causes saturation with white blood cells to help the response. But there can also be additional attack by corrosive RBC's. Should they be injured at the scene they will make perfect oxygen based toxin factories. The oxygen must be released in the ideal embodiment to our cells, not aerobic invaders, and must be released under all other circumstances in a microbial form. It dseems the latter need is embodded in the design of blood, although it may or may not be possible for the former.

But that is just the begginning. Suppose a red blood cell is attacked in the periphery, it will participate in exagerating initial oxidative damage, and maybe the endothelial (vessel) cells can control this response along with immune cell factors and inflammatory markers. But at that site, white blood cells will target the damage and then, through phagocytosis, identify threats. The WBC can then have plenty of adjuvant molecules to identify for antigen presentation.

But centrally, in the liver, spleen or marrow, old RBC are taken up and they are naturally eaten by phagocytes and the nutrients recycled.

So, RBC may be able to function as ideal sponges for invading microbes. Then, as viruses and parasites head into the nucleus-free RBC, they are probably rendered quite safe and they cannot reproduce. This invasion triggers cell damage and ROS generating pathways. Thus the intracellular parasite is captured, baked in toxins, broken down rendering internal to the RBC plenty of biogenic fractions. These are tagged as they flow around the body, and the damaged RBC are filtered and phagocytised by Antigen Presenting phagocytes. These can then identify the safe, toxin sterilised virus or bacterium and initiuate a relevant response.

Thus, RBC number allows billions of littlke 'sponges' to mop up intracellular pathogens. No nucleus, means no infection. Then, the damage causes them to be tagged for phagocytes, which can recognise the invader! Very neat.

In the RBC factories, the cell division of mother cells reveals a surprise - the daughter cells, containing in mammals no DNA, leave behind a mother cell with all the DNA. This is then immediately gobbled up by phagocytes! The immune system is constantly eating blood cells of the body, even before they have become blood cells propper. This seems astronomically wasteful, but then perhaps not. These resources can be switched. If the individual is suffering infection, the resources can all be switched to relevant immune cells from haematopoetic precursors?

http://www.medicalnewstoday.com/articles/96847.php

But what is the weakness of this system? Well, MALARIA parasite comes to mind. Where does that bug live? In the oxygen rich carriers of the blood stream. Clearly, it benefits from the available nutrients as well as 'hides' from the immune system, which it cannot really do since the vigourous phagocytosis ought to prevent it getting away with life in these cells - except that, of course, being an animal, the parasite like oxygen and is metabolically boosted. This means that being in RBC's confers a metabolic advantage like we suggested, as the maria parasite can overwhelm in numbers, which is energy and metabolism dependent, the immune response.

I checked and this parasite seems to almost only effect mammals, and mammals have no DNA in their RBC. Perhaps smaller RBC may be the solution?

Edit - I was surprised to find on the Tree of Life project http://itol.embl.de/itol.cgi that the organism behind maleria goes way, way back, though it couldn't have had quite the same targets. Smaller RBC would be of no use, they would need to be way smaller.

http://en.wikipedia.org/wiki/Malaria_parasite

1: Nat Immunol. 2007 Oct;8(10):1029-31. Links

Comment on:
Nat Immunol. 2007 Oct;8(10):1114-22.
Oxidative burst without phagocytes: the role of respiratory proteins.Bogdan C.
PMID: 17878909 [PubMed - indexed for MEDLINE]



1: Nat Immunol. 2007 Oct;8(10):1114-22. Epub 2007 Aug 26. Links

Comment in:
Nat Immunol. 2007 Oct;8(10):1029-31.
Respiratory protein-generated reactive oxygen species as an antimicrobial strategy.Jiang N, Tan NS, Ho B, Ding JL.Department of Biological Sciences, National University of Singapore, Singapore 117543.

The evolution of the host-pathogen relationship comprises a series of invasive-defensive tactics elicited by both participants. The stereotype is that the antimicrobial immune response requires multistep processes. Little is known about the primordial immunosurveillance system, which probably has components that directly link sensors and effectors. Here we found that the respiratory proteins of both the horseshoe crab and human were directly activated by microbial proteases and were enhanced by pathogen-associated molecular patterns, resulting in the production of more reactive oxygen species. Hemolytic virulent pathogens, which produce proteases as invasive factors, are more susceptible to this killing mechanism. This 'shortcut' antimicrobial strategy represents a fundamental and universal mode of immunosurveillance, which has been in existence since before the split of protostomes and deuterostomes and still persists today.

PMID: 17721536 [PubMed - indexed for MEDLINE]

http://bloodjournal.hematologylibrary.org/...ract/93/11/4006

Oxidative stress has been implicated in the triggering of apoptosis in neutrophils. Because red blood cells (RBCs) are well known to scavenge oxidants including H2O2, we tested the hypothesis that RBCs inhibit apoptosis of neutrophils by reducing intracellular oxidative stress. Apoptosis of neutrophils was evaluated by light microscopy and DNA gel electrophoresis. We found that coculture with RBCs protected against neutrophil apoptosis. Neither physical contact between RBCs and neutrophils nor the cellular integrity of RBCs was required to protect against neutrophil apoptosis. Neutrophil apoptosis was promoted by exogenous H2O2 but suppressed by catalase, indicating a role for H2O2 as a mediator of apoptosis. The protective effect of RBCs against apoptosis was due to catalase and glutathione metabolism because blocking of these antioxidant systems in RBCs attenuated the protective effect of RBCs. These results suggest that neutrophils are protected against apoptosis in the circulation.

-under normal circumstances, RBC's then play a basic role of limiting oxygen radicals in the vasculature. You can see many benefits to the humble red blood cell!

I'm interested in how RBC respond to infection and may trigger Antiogen Presenting Cells via phagocytosis.

Normally. I understand that macrophages actually inhibit APC after phagocytosis of cells, so it is important to find out what immune subsets deal with damaged RBC, and how RBC communicate damage.

As I build up my knowledge, certain features it may need to have, or benefit from, start to become clearer - here is what I wrote today at work, it will form the basis of further investigation:

RBC could be taking up path(ogen), path could cause trigger of surface receptors
on RBC, but block pro-apoptotic pathway, thus, the RBC is taken up by
macrophages and at spleen / marrow the RBC contains an attenuated virus or
other path. The absense of pro-apoptotic action causes the macrophage to
initiate cross talk with APC and and identification of alien material?

To that end, the normal phagocytosis of RBC by macrophages would
potentially help it identify what should, or shuoldn't be present in the
RBC.

RBC thus act as reporting systems and a kind of 'scout network' for the
immune system?

-well, its a start.

I looked then at how macrophages respond to infections and present them to other cells, such as Dendritic cells, to see if this would elucidate anything on how infected RBC *may* convey threats to immune cells. I was nothing less than astounded by the following, This was very exciting to read:

http://www.biochemsoctrans.org/bst/032/0496/0320496.pdf

It shows that macrophages that eat apoptotic cells shut off APC and block reaction and thus autoimmunity. The macrophage has a calming role on the immune system.

But what if the macrophage gets infected, as it can by micoplasmas (condensed parasytic bacteria without all the cell body components)?

That PDF shows that the macrophage can kill itself, and by initiating the apoptotic pathway, it also initiates mechanisms to kill whatever is in it. But, to then present the bug to the APC, such as a dendritic cell, which can go on and tell other cells what to look for and destroy, the macrohpage shows tremendous sophistication - a component called a 'bleb' is an autonomous bit of the cell that can break off from the cell body, and can excplore its environment and return to the cell body, refuse and thus forms a sort of 'intelligent goo'. These self powered organisms constantly pulse. The 'bleb' can break off from the macrophage, containing the infectious agent trapped within it, and this is passed into dendritic cells!!! (They then identify its structure in something analgalous to bug forensics)

That is just extraordinary.

Some more on those interactions:

http://www.jcb.org/cgi/content/full/155/4/501

PS signalling dual role and APC suppresion.

So, any relevance to Red Blood Cells?

Well apparently so. That 'blebbing' which is an extraordinary property of animal cells, being smartly, energetically self controlled bits of cell cytoplasm, are also features of RBC's - but - when RBC's are attacked by peroxynitrite.

Peroxynitrite may well be induced by infection, therefore, RBC may well present infected 'blebs' to fuse with relevant components in the Dendritic Cell's rogue recognition machinery - just like macrophages?

http://www.fasebj.org/cgi/reprint/19/3/416.pdf

Inhibitory effect of RBC's on fibrobrast (connective tissue and wound repair) proliferation.

http://www.blackwell-synergy.com/doi/pdf/1...3.x?cookieSet=1

Fibroblasts in turn communicate to macrophages that can control the remodelling by fibroblasts.

Ahh,

http://content.karger.com/produktedb/produ...p;file=cpb12373

Cytoadherence of Malaria-Infected Red Blood Cells Involves Exposure of Phosphatidylserine
Shigetoshi Eda, Irwin Sherman

Department of Biology, University of California Riverside


Address of Corresponding Author

Cell Physiol Biochem 2002;12:373-384 (DOI: 10.1159/000067908)



--------------------------------------------------------------------------------

Abstract

Phosphatidylserine (PS) is a membrane phospholipid which in intact cells is exclusively localized in the inner leaflet of the lipid bilayer. However, once cells undergo apoptosis or oxidative stress, PS molecules are exposed on the external surface of the cells and this contributes to their adherence to macrophages or endothelial cells. PS exposure on Plasmodium falciparum-infected red cells was determined by flow cytometry using fluorescein-labeled annexin V, which specifically binds to PS. Involvement of exposed PS in the adherence of malaria-infected red cells to endothelial cells was examined by in vitro cytoadherence assays. Infected cells exposed PS on their surface as the intracellular parasites matured to trophozoite and schizont stages. Adherence of malaria-infected cells to CD36, CD36-expressing Chinese hamster ovary cells, thrombospondin, and C32 amelanotic melanoma cells was inhibited by annexin V, whereas ICAM-1- and chondroitin sulfate A-mediated binding was not. Further, PS liposomes and glycerophosphorylserine, but not phosphatidylcholine liposomes and glycerophosphorylcholine, inhibited the binding of infected cells to CD36 and thrombospondin. In conclusion, these results demonstrate that PS exposed on the surface of malaria-infected red cells contributes, in part, to the adherence of P. falciparum-parasitized red cells to CD36 and thrombospondin.

------------------


-we were looking at Phosphatidyl Serine as a marker for tagging cells for phagocytosis - it is vitally dependent on PS to initiate the process. It now seems it is presented following infection of RBC, by RBC. this gets us closer to some of the assuimptions of RBC acting as a sacrificial means to absorb and present infections?

The infected macrophage then presents the infection to T cells and Dendritic cells?

If the macrophage sees no infection, it presents nothing, doesn't undergo apoptosis, and thus acts to prevent exposure of proteins to APC and helps prevent auto-immune reactions.


One also wonders if RBC are meant to absorb poisons? Drugs frequently get absorbed into RBC so effectively they cannot make it into the brain. RBC could remove toxins from infections?


damaged RBC targets for macrophage attachment and destruction-

http://links.jstor.org/sici?sici=0027-8424...TOR-enlargePage

Abstract

Macrophages specifically bind and internalize oxidatively modified low density lipoprotein (LDL) via the acetyl-LDL receptor and possibly one or more additional receptors jointly designated here as scavenger receptors. It is well accepted that these receptors are intimately involved in the formation of foam cells during atherogenesis. However, the normal physiological or pathophysiological role for these receptors has not been established. Oxidation of plasma membranes is a common accompaniment of cell damage and senescence. In particular, aged erythrocytes demonstrate peroxidation of their cell membrane lipids. In the present studies we show that oxidized human erythrocytes (treated with copper plus ascorbate or hydrogen peroxide) are bound and phagocytosed by mouse peritoneal macrophages in the absence of opsonizing antibodies. There was little or no binding of untreated erythrocytes. Oxidized LDL, but not acetylated or native LDL, inhibited this binding and uptake of oxidized erythrocytes. Inhibitors of scavenger receptor binding, including polyinosinic acid and fucoidin, also prevented binding of the oxidized red blood cells. We suggest that oxidative damage of erythrocytes results in the formation of lipid-protein conjugate(s) closely related to some of the conjugates found in oxidized LDL, making the oxidized erythrocyte a ligand for the macrophage scavenger receptors, apparently at a site distinct from that responsible for the binding of acetylated LDL. Oxidative modification of plasma membranes may represent a general mechanism that marks damaged cells for phagocytosis by macrophages.

A clear liquid O2 carrier that will replace blood transfusions one day. I saw this on a TV show a couple years ago. It's meant to sustain the patient till the marrow boosts RBC production back to normal. I forget the name of the doctor who developed it but he gave a demonstration by submerging a small mouse in a beaker filled with the liquid. The mouse was able to respire in the liquid. Not sure how it's development has progessed to this date.

Yes, that idea is quite an old idea. Efforts to make liquid oxygen carriers for pateients todate, as far as I am aware, have universally failed because they dont operate the right way in the body. In part this is because blood vessels need blood cells to regulate their diameter through a NO signalling pathway. We posted on that over on avant.

I'm not sure if any one can contradict this, but I was just looking at fat uptake by the lymphatic system. I'd suspect that the evolution of the lympth vesse;s originated to distribute both fat and cells to growth areas (and aid recycling). The lympth system is seperate to the oxygenation system. It strikes me that glucose is only dumped in the circulating oxygen network as an afterthought, and that energy is primarily supplied . Originally the oxygen network would have been oxygen rich seawater, possibly involving oxygen generating symbionts as found in some sponges and protists.

The oxygen supply is thus seperated from the lympthatic supply of hydrocarbon energy. That would mean, as we first hypothesised, there would be a pressure to seperate oxygen from energy in order to prevent it fueling protist competitors and other anearobes. Control over nutrients must be the primary immune system, and the best way would be to move oxygen independently to fuel.

A lympth like system would fit that bill, with vessels for seperately distributing oxygen an ideal anti-microbial embodiment. In the early eukarote, oxygen would be obtained directly from flagella-powered sea water circulation, whilst when captured in protist like cells, the nutrients in it would probably be distributed in special channels in between cell networks whose exterior may be able to get oxygen from water circulation? Thus either circulatory system is sort of the origin of lympth and blood vessels.

In humans, I believe RBC's act to block oxygen availablility even though, once transported by the lympth system, fat ends up transported in cholesterol packets along with dissolved glucose, in the blood. Thus energy and oxidant are supplied together although levels of either in solution are controlled as much as possible, and immune cells are heavcily invoplved in intercepting rogue packets of fat that may get infested. These turn into foam cells if there is dysregulation of the whole thing, and especially when fat gets oixidised in the wrong place.