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Gallo's theory and resources

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  • Gallo's theory and resources

    So, this is an attempt to put the 2007 paper, by Gallo & team, on some of the key elements of the cause of rosacea, in ordinary language, so that more people can read it and understand it. I am pretty confident that my interpretation is all correct, but I am not a scientist, nor do I have a science background, so if anyone who is/does finds errors, please point them out so they can be corrected.
    “Cathelicidins” are part of our immune system. They can kill microbes (they are 'natural antibiotics'), but they can also set off inflammation. The fact that the kind of inflammation which cathelicidin can cause is similar to that found in rosacea, was the original motivation for the team to investigate a little further, to see if there might be some real connection between the disease and this biological component.

    In this study, they first measured the levels of cathelicidin in rosaceans, as compared to normal individuals. In rosaceans, a very high level of cathelicidin was found, and also it was found to be located all through the top layer of the skin, whereas in normal individuals they found very little.

    The following pictures display this. To make the pictures (concentrating on (a), i.e. the two top lines of boxes) they apply to a slice of skin something that can 'see' cathelicidin; then they stain the slice, so you can see exactly where the cathelicidin is located. On the left two pictures in the top row, it shows rosacea skin. The red staining is the cathelicidin being picked up (forget all the blobs and lines and structures and strata; that's the detail of the skin. The important thing is the red patch/layer). The middle picture is just a more 'zoomed in' version of the left-hand one. The right-hand picture shows normal skin, and the point is that there is almost no red-staining. The row below is just a 'control' picture.

    (b) is a graph showing the levels of cathelicidin found in three rosacea individuals, and three normal individuals. You can see that in all three rosaceans, levels are considerably higher than in the normal individuals, who seem to have levels pretty close to zero.

    The pictures of(c), at the bottom right, are based on the same basic 'staining' technique as (a). Only here, they are not measuring cathelicidin itself, but cathelicidin mRNA – which is to say, how much the gene for cathelicidin is being expressed. Again, you can see a distinct difference, of red staining in one case, versus very little in the other.
    For the next part of the study, they looked at what kind of cathelicidin is present in rosacea skin. As mentioned at the beginning, cathelicidins can be antimicrobial, or inflammatory. Now, which they are depends upon their size/length, and shape. In very general terms, the longer/bigger versions of cathelicidin are inflammatory, whereas as they get shorter, they're more antimicrobial. This isn't a completely clean distinction, but a general rule – so, the longer forms can still kill microbes, and some of the shorter forms can still initiate inflammation.

    What the graphs below are showing are the levels of each kind of cathelicidin. Moving from left to right is moving from smaller to bigger. The higher the spike, the more there is. The top three graphs are for rosaceans, the bottom three are for normal individuals. There's a lot of 'noise' in the graphs, but broadly speaking, you can say that where there is a reasonable spike, it is registering a distinct kind of cathelicidin.

    The first, most obvious thing to notice is just how much more spiky are the graphs for rosaceans than those for normal individuals. The second thing to notice are the big spikes on the far right of each of the rosacean-graphs. This corresponds to LL-37, the 'standard' form of cathelicidin. This is the most inflammatory form, and its apparent from these graphs that we've got a lot of it – it is literally off the scale in two of the samples. The third thing to notice is that, as recorded by all those spikes, we've got high levels of lots of different kinds of cathelicidin that just aren't present in normal skin.
    Cathelicidin begins life in an inactive form (called hCAP18). It is activated by kallikrein, particularly kallikrein 5 (also called “stratum corneum tryptic enzyme”/SCTE). More precisely, what happens is that kallikrein 5 'chops off' part of the inactive form; and once it is released in this way, it becomes active. This active form is LL-37.

    In fact, this chopping up just keeps on going, and that is how you get the shorter/smaller versions of cathelicidin – kallikrein just keeps chopping away.

    So, if rosaceans have lots of cathelicidin, and it is kallikrein 5 that activates it/generates the different smaller forms, it is natural to propose that we must have lots of kallikrein 5. So the next step in the study was to check this out. They found that, indeed, there were high levels of kallikrein in rosacea skin compared to normal skin - and that it is located in the same places as the cathelicidin (i.e. so it is able to act upon the latter).
    Moreover, although there is a small amount of kallikrein in normal skin, it is located right at the outer layer of the skin. It has a purpose there, namely to help in the shedding of old, dead skin cells. In rosacea skin, by contrast, it is located in the deeper layers, where it really has no business being.

    This result is what the top pictures (i.e. (a)) are showing, below. Once again, how they generate these pictures is to get a slice of skin, treat it with something that can 'see' kallikrein, and then take a picture of the slice with a method that shows up that kallikrein. What you're looking at is essentially a vertical slice of the skin (at the top, its the outer layer, and then it goes deeper as you go down). The left, green box shows cathelicidin; kallikrein 5 in the middle box (red); and the two pictures merged together on the right hand side. As you can see, the top row of boxes, showing the rosacea samples, displays a very distinct patch both for cathelicidin and kallikrein; whereas the bottom row, showing normal skin, is much more faded. (In the supplementary data, there are lots more of these pictures, showing it even more distinctly).

    As for what the other two parts (i.e. (b) and (c)) of this diagram are showing, well, kallikreins are a type of “protease”. What (b) is showing is total protease activity, again using the same kind of 'staining' technique. If kallikreins are higher in rosaceans, you'd naturally expect total protease activity to be higher. And indeed, again (although these pictures are a bit rubbish) you can see a difference between the rosacea samples, and those from normal skin. The two different pictures (green and blue) are just those generated by two different methods.

    What (c) is showing is the result of an experiment which is narrowing down the type of kallikrein we're talking about. Different kallikreins (like number 5, or number 7, and so on) have a slightly different chemical make-up. That means that they respond differently in the presence of other chemicals, and so you can work out the identity of some kallikrein in a sample, by how they are responding to a given chemical. More specifically, the chemicals they use are one's which 'kill' or 'put to sleep' or 'inhibit' kallikreins of a particular type. In the graph of (c), the bars represent the fact that kallikreins are still alive. So, they're not alive in three cases – with the “mix”, with the aprotinin, and with the AEBSF. Since these three inhibitors inhibit “serine” proteases, it shows that the sample contains serine proteases. And kallikrein 5 is a serine protease.
    OK, so now we know that rosaceans have high cathelicidin and high kallikrein 5. That's pretty interesting, especially since it is known that cathelicidin can be inflammatory. Its suggesting that our rosacea might be caused by this extra cathelicidin (itself caused by the extra kallikrein 5).

    But maybe that's not right. Cathelicidin is expressed by inflamed tissue (other experiments have shown this), so maybe the cathelicidin isn't the cause; rather, its the other way around – we've got high cathelicidin because we've got inflamed, rosacea skin.

    This is where the final parts of the study come in. They basically aim to come at it from the other end – to reproduce the conditions found in rosaceans (high cathelicidin, high kallikrein) and see what it yields.
    First off, they took the cathelicidin forms that were highly present in rosacea skin (like LL-37, as well as some others) and basically put them in a dish with some skin cells. They did the same with the cathelicidin forms found in normal skin. In the first dish, they found that the skin cells were caused to express inflammatory “messengers” (namely, IL-8). In the body, that would mean that you kick-start the process of inflammation – these messengers tell other cells there is a problem, and basically get the immune system into gear. Nothing happened in the dish containing 'normal' cathelicidin.

    OK, next up, they took these rosacea-type cathelicidins and injected them into mice (I know, poor mice. God have mercy on us). 48 hours after injection, the mice's skin starts showing signs of something that looks very much like rosacea, as you can see from the photograph contained in the diagrams below. (b) shows what happens when you inject rosacea-skin cathelicidin on the one hand (left side), versus the kind of cathelicidin found in normal skin (right side). (The supplementary data has more good pictures, showing the consequence of different dosage-levels, and so on. The boxes below the photos, here, show more staining-type pictures of slices of the different skin samples. They're picking up inflammatory cells, but its so messy, you barely know what you're looking at).

    By the way, (a) is the graph from the first experiment, showing the levels of IL-8 produced by skin cells, when in the presence of two rosacea-skin cathelicidins (LL-37 and FA-29) and other, normal ones.

    OK, next up, more mouse-sacrifice. They deleted the genes in mice that code for cathelicidin, so that these mice can't make any. They then applied irritants to the skin of these mice, and compared the reaction to those of normal ones. c) shows the result, via another staining-type procedure. No doubt there's something there, but personally I can't really make out what I'm looking at. (d) is a lot more unambiguous. This is a graph showing measurements of a particular inflammatory cell, which gives you a rough measure of how much inflammation occurs. The mouse with no cathelicidin (left) shows very low levels of this inflammatory cell; the one with cathelicidin shows considerable levels. So that shows that, indeed, cathelicidin can promote inflammation.

    The next experiment was similar. They mice and deleted the gene that codes for an inhibitor of serine proteases (such as kallikrein 5). Because of the lack of the inhibitor, these mice would therefore have more kallikrein – just like us rosaceans. What they looked at in these mice, was the kind of cathelicidin they had, and found it to be LL-37, the type we have in abundance. This firms up the causal link between excess kallikrein, and excess cathelicidin (of abnormal kind), i.e. it shows that too much of the former is going to cause too much of the latter. This is shown in the graph (e). The only relevant spike is the one with the big triangle over it. The top line is showing the situation for mice without the inhibitor. (Note that the graph as a whole has 'scrolled to the right', so to speak, so whereas LL-37 was on the right in the former graphs, its now on the left; and to its right are just really big/large/long forms, of no interest).

    Next they injected kallikrein 5 into mice, at a level that reproduces the amount found in rosaceans' skin. Redness and inflammation result. (Figure (f) shows this, in more staining-type pictures. The top box displays a slice of skin that is just overrun with red-stained matter. The bottom box, where the kallikrein is inactivated before injection, shows a slice of basically normal skin, with all the detail and structures visible. The graph to the right is recording cathelicidin, and shows a big spike in the predictable place).

    Finally, (g) and (h) are displaying comparisons of the injection of kallikrein 5 into mice without (left) or with (right) cathelicidin. A lot more inflammation occurs in the mice with cathelicidin, for reasons which will now be obvious. Once again, the pictures (g) are a bit unclear, but the graph recording the levels of a particular inflammatory cell (h) leave no room for doubt.
    So, these are the experiments on which Gallo's theory are based. We end up with a whole heap of tortured and dead mice, but some pretty solid evidence about rosacea. There's room for more questions to be asked – but questions based around these results.

    The rest of the paper fleshes things out a bit.

    They note that, since cathelicidins are antibiotics, and rosaceans have abnormal cathelicidins, its possible that in addition to the inflammation that results, we might also have an impaired ability to fight microbes that inhabit the skin. For example, it has been observed that rosaceans have more demodex mites than normal individuals. Well, maybe (the authors speculate) that's because our abnormal cathelicidins aren't as effective at keeping them under control.

    They also note that tetracycline antibiotics – which have been a mainstay of rosacea treatment – indirectly inhibit protease activity in the skin. So, their theory explains why this would be effective.

    Finally, there is this. Kallikreins do not just active/chop up cathelicidins. Their main job in the skin seems to be to break down the ties holding skin cells together on the outer layer, so that they can slough off. To much kallikrein, therefore, would make this happen too quickly, and the result would be an impaired skin barrier. Rosaceans do very often have skin that is sensitive to irritants, so once again, Gallo's theory would explain this phenomenon.
    Last edited by TheMediumDog; 18 September 2009, 05:01 AM.

  • #2
    This is a collection of papers relating to aspects of Gallo's theory. I don't actually think Gallo's theory is the full story. I think he's uncovered part of the mechanism. Still, its all useful, to build a picture.


    1. Tips for how to read.
    2. The papers. (Titles are in bold. I've given a summary beneath many, sometimes long, sometimes short, depending mostly on how important I think they are. If you put the title into Google, you'll get the original paper - I can't link to them, since there's a limit on the number of links in a post. They are in date order. I've split them up into sections, by their main focus - main areas are given just below. Obviously they overlap quite a bit).

    Order of papers:

    On cathelicidin
    On kallikrein
    On hormone control of kallikrein
    On PAR's (Protein-Activated Receptors)
    On Vitamin D3
    On inhibitors of kallikrein
    - general
    - Nafamostat
    - SLPI
    - Soy
    - Tetracycline antibiotics
    - Zinc
    On changes in the skin barrier / desquammation / loss of integrity

    Note that in a couple of places I've written in coloured letters. That's for stuff which is just so incredibly important, that it should have your attention....

    ...It's not finished. I will keep adding and refining, and cleaning it up, as time goes by....

    1. Tips:

    At first, all these names, concepts, strange terms, and multiple theories are really confusing. Obviously it takes a bit of time and patience to make out the land beyond the blizzard. One thing I've found helpful is to latch on to one thing, that seems particularly connected with your individual condition. With this relatively secure 'rock', you can then branch out.

    The 'Introduction' and 'Discussion' sections of papers are often the easiest to understand. The 'Results' section is often quite difficult, because its bitty, and will be filled with details of experimental procedures, acronyms and so on. The 'Materials and Methods' sections can just be skipped.

    When first starting out, its a good idea to have Wikipedia on hand. Check every term you don't understand. At first, this will make things very slow, but you'll quickly pick things up. The most difficult things to understand are often the basic concepts – like, for example, the way cells communicate through producing chemicals that switch on receptors; or, like, the fact that a gene gives rise to a protein, which then does stuff – but you learn these along the way. Having said that, I have found that a quick grounding in the basic concepts from a school biology textbook to be really useful, and only took a few days.

    I've found that its really not a great idea trying desperately to absorb this information in the hope that you might draw something out to help with your latest flare. That is just frustrating, because this is all at one remove from our actual disease. This stuff needs to be read with a longer-term view.

    2. Papers.

    Papers focussed on Cathelicidin

    (1993) The Expression of the Gene Coding for the Antibacterial Peptide LL-37 Is Induced in Human Keratinocytes during Inflammatory Disorders

    Cathelicidin (LL-37) is expressed by keratinocytes (skin cells). Whereas you don't find cathelicidin in normal skin (i.e. the gene doesn't express/produce the protein), you do find it expressed in lots of different inflammatory skin disorders, from psoriasis to lupus to atopic dermatitis.

    (2000) Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells

    Cathelicidin, especially the longer forms like LL-37, have inflammatory effects (which is to say, in other words, that they stimulate parts of the immune system). But how exactly do they do this – what is the mechanism? This study reports results showing that at least in part, LL-37 works through a receptor, called formyl peptide receptor–like 1 (FPRL1). What does this mean? Well, the cells of the immune system have to be set into action, and told where to go, via chemical signals. They have 'receptors' which respond to particular chemical signals; and so when those receptors are switched on, they know what to do. LL-37, then, is able to activate some of these receptors (like FPRL1), thereby mobilizing parts of the immune system into action.

    The specific parts of the immune system activates via these receptors, reported in this paper, are “monocytes”, “neutrophils” and “T lymphocytes”. Each of these has a particular job. In combination, they would be responsible for a good proportion of the inflammation of rosacea.

    (2001) Cutaneous Injury Induces the Release of Cathelicidin Anti-Microbial Peptides Active Against Group A Streptococcus

    Cathelicidin is produced in the skin following wounding, and following the invasion of microbes.

    (2001) Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3

    The cathelicidin produced by neutrophils (which are general immune-system cells; this is in contrast to keratinocytes, which are the basic form of skin cell) is processed into the active form by proteinase 3 (which is also stored in neutrophils).

    This is quite an interesting study. In contrast to other studies reporting that cathelicidin is activated/processed by kallikreins, it is pointing to a different enzyme – i.e. proteinase 3. I think it may be that this is the cathelicidin-processing enzyme specific to neutrophils. I.e., they have their own, slightly different activation mechanism (namely, proteinase 3). Or it may be that proteinase 3 activates, whilst kallikreins further process; or there could be a conflict in the data; but I don't think so.

    (2003) Antimicrobial and Protease Inhibitory Functions of the Human Cathelicidin (hCAP18/LL-37) Prosequence

    A bit derivative this one. When cathelicidin is originally activated, it is broken off from a larger 'precursor' protein. (hCAP18). That obviously leaves the rest of the precursor protein floating around. But it, too, can act against microbes. It also inhibits a certain protease (not kallikreins, but cysteine proteases).

    (2003) Mast Cell Antimicrobial Activity Is Mediated by Expression of Cathelicidin Antimicrobial Peptide

    Mast cells (a component of the immune system, involved for example in the release of histamine) contain cathelicidin (we've already seen, above, that both skin cells, and other immune-system cells called neutrophils also contain cathelicidin). And mast-cells' cathelicidin is part of how mast cells are able to be antimicrobial

    (2003) An angiogenic role for the human peptide antibiotic LL-37/hCAP-18

    This one is quite directly relevant to us, it would seem. Cathelicidin promotes the growth of new capillaries. The exact mechanism by which it does this is a little bit abstruse, but simple enough – it activates a little switch on the capillaries, which gets them to grow (obviously, its more complicated, but I think this is still an accurate simplification). But there are also other more roundabout pathways, in addition, but which it promotes angiogenesis.

    (2004) Postsecretory Processing Generates Multiple Cathelicidins for Enhanced Topical Antimicrobial Defense

    This is an important one, because it is demonstrating an important basic principle – that cathelicidin is activated and changes its function (from inflammatory, to antimicrobial) insofar as it is processed/cleaved. And that this activation & processing is done by an enzyme. It also finds cathelicidin in sweat.

    (2005) Keratinocytes Store the Antimicrobial Peptide Cathelicidin in Lamellar Bodies

    The cathelicidin produced by skin cells (it can also be produced by cells that only arrive at sites of inflammation, like “neutrophils” for example) is stored mostly in the granular layer of the skin (the second layer down from the surface, just below the stratum corneum). Specifically, it is stored in cells called “lamellar bodies”, which are little bubbles containing lipids, and whose job is to replenish the skin barrier (with the lipids) when it is disrupted. (Heard of all those cosmetic products containing "ceramides" and "lipids"? Well this is where they come from in their natural form). Thus, cathelicidin forms part of a wider defensive mechanism of the skin, to disruption: namely, restoring the barrier, and also produce inflammatory/antimicrobial cells, to deal with any invading pathogens.

    However, this is not all, and I think, personally, that this study contains a detail of first rate importance, at least for some forms of rosacea.

    OK, so, cathelicidin is stored within a particular vesicle within skin cells. What this study also shows is that skin cells are capable of internalizing bacteria. These bacteria then head off towards the vesicle containing the cathelicidin, and thereby will be killed.

    The following picture shows the co-localization of bacteria with cathelicidin within the skin cell:

    green for cathelicidin, red for bacteria, and yellow for, I think, exact co-localization).

    The reason this could be significant is that it could supply the cause of the high levels of kallikrin/cathelicidin, which Gallo's theory otherwise doesn't have a real explanation for. How? Well, what if the bacteria are internalized but are not fully destroyed? If, indeed, they remained within the skin cell, therby provoking a continual, but ever-ineffective response?

    This is slightly more than mere idle speculation, since there is, for example, a study
    ((2007) The role of chlamydia pneumoniae in the etiology of acne rosacea: response to the use of oral azithromycin) which found there to be antigens of this bacteria in skin samples from some rosaceans ('antigens' being tell-tale bits on the surface of a bacteria which both stimulates the immune-system, and gives you a good idea which bacteria it is) as well as antibodies (what the skin cooks up in response to antigens. If you've got antibodies to some antigen, it proves that the antigen has been around, and, therefore, the bacteria). Chlamydia pneumoniae lives by entering host cells, hiding out, and replicating.

    However, it may not be chlamydia but some other bacteria - this case just proves the point of principle. And you've got to bear in mind that 95% of bacteria have been, until recently, unknown because we've not had the techniques to study them.

    In a situation where the immune-system was depressed (maybe you're run down, or whatever) and maybe if your skin was compromised (harsh cleanser, say) a bacteria could enter, and then set up camp.

    This, moreover, would explain the fact, shown in Gallo's 2007 study that kallikrein/cathelicidin is expressed in the deeper layers of the skin, in rosacea. The crucial point to bear in mind is that lamellar bodies (which, recall, contain the cathelicidin) only get released from skin-cells quite late on in the process of skin-cell development. (They contain lipids, recall, and these lipids are what forms the impermeability barrier at the top of your skin. So, the lamellar bodies are released near the top, and then spill their contents around). Further down deep, they're still inside the skin cell. So, you might think, if the kallikrein/cathelicidin is being expressed down deep, this must be going on inside the skin cell. But then its natural to think its doing so in response to a pathogen that is in there too.

    Keratinocyte Production of Cathelicidin Provides Direct Activity against Bacterial Skin Pathogens

    More on this theme of the internalization of bacteria, and their combating by cathelicidin.

    (2005) Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities

    Cathelicidin can exist in lots of different forms, and these forms do different things. They are 'processed' (or degraded, or cleaved) from longer to shorter forms. When they start out (as LL-37) they mostly stimulate inflammatory mechanisms. The shorter (i.e. more processed) forms are more antimicrobial.

    (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin

    This is an important one.
    This builds on prior work showing that, as cathelicidins are processed to shorter forms, the balance of their activity moves from inflammatory to antimicrobial. It identifies that this processing is done by kallikrein's 5 and 7.

    It establishes that LL-37 is not the only, or indeed the predominant form of cathelicidin in the skin (in contrast to the situation within neutrophils, where it is), as you can see in this nice graph:

    What this is showing is the quantity of the various cathelicidins of different size – thus, LL-37, which is big/long, is represented by the spike on the far right. As we move left, the spikes occur where there are significant levels of cathelicidin of that particular size. Its apparent that LL-37 is by no means the most abundant, being only 13.7%. Keep in mind that this is in normal skin. In rosacea skin, the proportions are very different.
    And the following schematic diagram gives a good picture of the proteolysis of cathelicidin:

    At the top, we have the 'inactive precursor' (hCAP18), i.e. the thing from which cathelicidin comes. The first arrow shows that stratum corrneum tryptic enzyme (SCTE/kallikrein 5/hK5) splits off cathelicidin (LL-37) from this precursor, and the remaining stages show the shorter cathelicidin forms that occur. The square boxes with 'T' shaped lines refer to inhibitors of kallikreins.

    A couple of things are worth noting. First, since SCTE both activates and degrades cathelicidin, one might expect that high levels of SCTE would just generate lots of the shorter, antimicrobial forms. Indeed, the study contains an experiment with mice lacking the gene to inhibit SCTE, and that is what happens. So how come rosacea – where there's lots of inflammation – is associated with high levels of SCTE. Something isn't right here.

    Second, it is mentioned that SCCE/kallikrein 7 is less able to degrade the longer forms, and better with the shorter ones, and that therefore it might serve to finally inactivate cathelicidin – i.e. make it so short that it no longer does anything.

    Third, the possibility that other proteases or kallikreins might be involved in activating/degrading cathelicidin is mentioned.

    (2007) Host Defense Peptide LL-37, in Synergy with Inflammatory Mediator IL-1β, Augments Immune Responses by Multiple Pathways

    This article outlines the mechanisms by which cathlicidin stimulates the inflammatory/immune response. (It is very difficult, being crammed with abbreviations). There are many pathways by which this occurs (amplifying some, suppressing others), so the overall effect is a specific modulation of the immune response.
    Note that this paper also (like 2001, “Human cathelicidin...) says that cathelicidin is cleaved by proteinase 3.

    (2007) The yin and yang of cathelicidins: how the innate immune system drives skin disease

    An easy-reading overview of current knowledge on how cathelicidin contributes to skin disease

    (2007 Review) Expanding the Roles of Antimicrobial Peptides in Skin: Alarming and Arming Keratinocytes

    Short review of the state of knowledge about cathelicidins circa 2007, basically just emphasizing that they don't just kill microbes, they also stimulate the innate immune response. Includes this interesting schematic diagram of the pathways by which cathelicidin signals further inflammatory processes:

    So, for example, it up-regulates various interleukins (IL-6, IL-10, and so on), which are “messenger” molecules, modulating the inflammatory response in different ways.

    If you look, you'll also notice that a drug which modulated G-Protein-coupled receptors would also be pretty handy, because it seems to be crucially involved in the pathway. A company is presently working on such a drug for rosacea.

    (2008) Innate barriers against infection and associated disorders

    Interesting review which sets cathelicidins in context. It gives an overview of our immune system, and explains the role of things like cathelicidin, compared to other elements. Good background information, although it is not all completely relevant. Rosacea is brought in at the end.

    (2008) Mast Cell Cathelicidin Antimicrobial Peptide Prevents Invasive Group A Streptococcus Infection of the Skin

    Mast cells, which are located close to blood vessels, are involved in various immune-system- and inflammatory processes, like recognizing/killing bacteria, attracting immune-cells (like “neutrophils”), and increasing capillary permeability. (They are involved in releasing histamine, for example).
    They express cathelicidin, which plays an important role in MC's ability to do these things. Moreover, some of the cathelicidin they express is different from that produced by keratinocytes (skin cells).

    (2008) Antimicrobial peptides and the skin immune defence system.

    An overview of the research knowledge, as of 2008. One of the key overviews that basically explains everything. Rather technical though.

    Secondary – studies containing info on cathelicidins, but which is less directly relevant to us rosaceans

    (2003) The Antimicrobial Peptide LL-37 Activates Innate Immunity at the Airway Epithelial Surface by Transactivation of the Epidermal Growth Factor Receptor

    The airways are obviously covered in 'skin'. And there are lots of chances for pathogens to try to invade through this route. So unsurprisingly, cathelicidins have been found to be active in this location. This study just shows that the cathelicidin here stimulates various bits of the immune system at this location.

    (2005 Ab) Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk.

    Cathelicidin is found in human milk. It presumably provides defense against unwanted bacteria in the milk (helping protect the baby).

    * * * * *


    (2003) Expression and Localization of Tissue Kallikrein mRNAs in Human Epidermis and Appendages

    There are 15 different kallikreins, and most of them occur in the skin (and many also in sweat-, sebum-, and hair glands). Their inhibitor is also expressed in the same location, and it may be that through expressing various different combinations and balances of the kallikreins, and also the inhibitor, the body is able to regulate the kind of proteolytic activity that occurs.

    (2004) Epidermal Lamellar Granules Transport Different Cargoes as Distinct Aggregates

    This study provides information on whereabouts in the skin kallikreins are stored, and released from. Namely, Lamellar Granules/Lamellar Bodies, which are located at around the middle of the epidermis (itself the top of the three basic layers of the skin). These granules contain quite a number of different goodies (including cathelicidin, as shown in the above 2005 study, 'Keratinocytes store...; also building materials for the outer skin layer, and some other stuff. Cathepsin, a protease, is mentioned. Although this isn't thought to be involved in processing cathelicidin, its something to keep an eye on), and what this study says is that they are all stored in different compartments.
    The Lamellar Granules/Bodies are themselves a component of the big basic skin cell – the keratinocyte. At a certain stage of progression up through the layers of the skin, these lamellar granules release their various contents into the surrounding space. There is an order to this release – different components are released at slightly different times. And correspondingly, these different contents are found in different layers of the skin.
    It must be said, given that both the elements (cathelicidin and kallikrein) that are supposed to be involved in the pathology of rosacea are stored in LG's, they're of some interest.

    (2005) Quantification of Human Tissue Kallikreins in the Stratum Corneum: Dependence on Age and Gender This useful article gives information of the amount of the different kallikreins present in the skin, including the variation among sex and age-groups. Note, though, that according to Gallo, rosaceans can have 500 times higher levels than normal people, so these numbers aren't an accurate guide for us. Interestingly, the most abundant kallikreins are #8 and #11 (rather than #7 and #5). Anyway, they're unclear on what all these other kallikreins do.

    (2005) A Proteolytic Cascade of Kallikreins in the Stratum Corneum

    Kallikreins activate cathelicidin, making them of interest to us. Aside from this one of the main jobs of kallikreins is to eat away at the structures holding together dead skin cells at the top layer of the skin (corneocytes) so that they can come off, or be shed.
    One process of obvious interest to us is how kallikreins get into their active state. This apparently isn't known too well, and so this study aims to shed some light, and also characterize their activity a bit better. (By the way, in all these experiments with kallikreins, they often need to use inhibitors of kallikreins for some purpose. Naturally, you always wonder whether any of these experimentally-used inhibitors could be applied topically. Often not, because they're toxic, or the molecules are too big to get through the skin. But here they use Zinc Sulphate in one experiment, which is small, and non-toxic, and has been used with some success in psoriasis. I think it may be irritating, though).

    Anyway, they begin as pro-forms, and the different kallikreins are involved in an activation “cascade”, meaning that one activates another, which activates another, and so on. Kallikrein 5 (stratum corneum tryptic enzyme, the one identified as 'our main enemy') is unique in being able to activate itself. One should not forget Kallikrein 14, which is more powerful than kallikrein 5 and can activate it, but is present in lower quantity.

    One quite interesting thing mentioned in this study is the following. Kallikrein's 7 and 14 work best at acidic pH, which is the usual pH of the stratum corneum. However, apparently kallikrein 5 works best at alkaline pH (at least “for cleavage of small peptides”). In rosacea, pictures show kallikreins running amok all over the place; that is to say, deeper down in the skin where presumably, it is more alkaline. So just maybe, this narrows down our target to kallikrein 5 specifically. Anyway, the significance of this in the present context is that it means that kallikrein 5 'auto-activates' first, deeper down, and gradually activates the other kallikreins, as we move upwards. With the pH getting lower, the higher we get, these kallikreins then set to work.

    There is still a lot of work to be done on kallikreins.

    (2006) Specificity Profiling of Seven Human Tissue Kallikreins Reveals Individual Subsite Preferences

    The different tissue kallikreins can be put in groups, according to where they mostly occur in the body. Data suggests that some kallikreins are involved in different diseases, like prostate cancer (hK3), hypertension (hK1), dental diseases (hK4), central nervous system inflammatory diseases (hK6, hK8), and skin diseases (hK7).
    What the different kallikreins do depends on their structure, and this study provides some detailed technical information on the structure of some of them.

    (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin

    See the same study under the Cathelicidin section.

    (2007) LEKTI Fragments Specifically Inhibit KLK5, KLK7, and KLK14 and Control Desquamation through a pH-dependent Interaction

    Kallikreins can be inhibited, and the body produces the means to do so (so that, through the control of the levels of each, it can regulate what goes on). This study shows that, in the skin, a protease inhibitor called LEKTI (or the mouthful, “Lympho-epithelial Kazal type inhibitor”) does so.

    There is a skin disease (Netherton's syndrome) in which people don't produce LEKTI. It is characterized by a really poor, degraded skin barrier. This illustrates the fact that – whatever else they do – kallikreins are involved in degrading/proteolysing the components that hold together the skin cells in the stratum corneum. In this skin disease, they do this far too much; hence the poor skin barrier.

    This paper describes the processes leading to the production of LEKTI (actually, its a family of lots of different fragments, each slightly different). One element centrally involved is called “furin”. It also demonstrates that the LEKTI-inhibition of kallikreins is governed by pH – at a lower pH level (5), kallikrein is, so to speak, released from the claws of LEKTI. This indicates what is supposed to happen, namely that kallikrein's are released near the outer layer of the skin, where it is more acidic, to do their work of detaching skin cells (by degrading corneodesmosomes). We get a lovely diagram of all this in this study. Obviously kallikrein doesn't really look like Pac Man, its just schematic:

    If Gallo's theory is correct, we should be pretty interested in this stuff, because surely at least one explanation for why we have too much kallikrein could be that we have too little LEKTI. On the other hand, we don't have Netherton's, so presumably something different is happening with us (although apparently, and interestingly, Netherton's can also be characterized by “chronic inflammation”.

    As a second matter, I think it is well worth exploring the connection with the pH control of kallikrein. A possibility one could take seriously is: bacteria residing within the skin are lowering its pH through their metabolism, to a point where it begins to over-activate kallikrein. One might even have the makings of the necessary 'loop' required to keep things going, if these bacteria preferred a low-pH environment, and if the activated kallikrein-cathelicidin were to lower the pH (e.g. through disruption of the barrier etc). Obviously this is all speculative. But a cause does have to be found from somewhere.

    (2009) Identification of Lympho-Epithelial Kazal-Type Inhibitor 2 in Human Skin as a Kallikrein-Related Peptidase 5-Specific Protease Inhibitor

    Strictly, this only relates to the palms, but still. The study reports that they found another inhibitor (to go along with LEKTI) of kallikrein. Specifically, LEKTI-2. And it inhibits kallikrein 5 very precisely, as opposed to other kallikreins.

    So, one might bet that, in facial skin, there is an analogous inhibitor, maybe there is even a family of them.

    In the paper, there is also a somewhat interesting comment, about the way that LEKTI-2 expression is modulated by mechanical force. (They're talking about thick skin on the palms. Maybe repeated rubbing etc upregulates expression of LEKTI-2, which means suppressing kallikrein 5, which means less desquammation). One can imagine a story for how a rosacea case begins that might use this property. But this is just speculation.


    (1980) Local kallikrein and trypsin responses in the rat

    Old experiments on rats, to do with kallikreins and their inhibitors.

    Abstracts only

    (1995) Evidence that stratum corneum chymotryptic enzyme is transported to the stratum corneum extracellular space via lamellar bodies

    Much more on this above.

    Human tissue kallikreins: a new enzymatic cascade pathway?

    Details about tissue kallikreins.

    (2008) Increased basal transepidermal water loss leads to elevation of some but not all stratum corneum serine proteases.

    This study shows that elevated proteases are present in even mild cases of increased skin dehydration. The study is done by a company, who presumably have the aim of convincing such people that they need to buy some product they'll produce. The usual capitalist imperative – convince people they've got a disease; sell them the drugs.

    (2009) Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases.

    It would be nice to have this one – basically an overview of the current knowledge on proteases (like kallikrein) and their inhibitors. Mind you, a lot of the stuff thats relevant to us is freely available.

    * * * * *

    Hormone control of kallikrein

    There's no particular reason to think that rosaceans' excess kallikrein is due to hormone imbalance, but it is nevertheless of interest that kallikreins seem to be controlled in part by hormones (although the studies mention that many other factors enter into their regulation).

    (1987) A secretory protease inhibitor requires androgens for its expression in male sex accessory tissues but is expressed constitutively in pancreas.

    This old study shows that a protease inhibitor to be under testosterone control. This is of very limited relevance, since the inhibitor may very well not even be expressed in the skin

    (2006) Effect of Testosterone Administration on Serum and Urine Kallikrein Concentrations in Female-to-Male Transsexuals

    This study shows kallikreins to be under hormone control. This study focuses on testosterone, and finds many of the kallikreins (including #5 and #7) to be affected by testosterone levels. The thing is that its such a particular case (female-to-male transsexuals receiving testosterone treatment) that its difficult to know where to go with it.

    Abstract only

    (2006) Serum and urine tissue kallikrein concentrations in male-to-female transsexuals treated with antiandrogens and estrogens

    This is very similar to the above 2006 study, except from the other side. The finding again seems to be that testosterone levels (or at least the balance between male- and female- sex hormones) affects kallikrein levels. In particular, lower relative testosterone levels seems to lower kallikrein levels.

    (2008) Regulation of human tissue kallikrein-related peptidase expression by steroid hormones in 32 cell lines.

    Its a pity that only the abstract of this is available for free, because it seems very thorough, although its very much a lab experiment rather than in the body. One can't see which hormones are regulating which kallikreins, for most of them.

    * * * * *


    PAR's (or Protease Activated Receptors) are not part of Gallo's theory. However, they do figure in another theory of the causes of rosacea, and it seems to me that these fit together.

    (2006) Proteinase-activated Receptors, Targets for Kallikrein Signaling

    This study reports that kallikreins, and kallikrein 5 in particular, is capable of activating PAR-2.

    (2009) Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome

    This is very interesting, because it shows that kallikrein 5, acting via PAR-2, brings about a host of inflammatory processes.

    * * * * *

    Vitamin D

    (2007) Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism

    Vitamin D has involvement in the expression of cathelicidin. There are a few of mechanisms involved. First, there is this process: there are certain cells (“Toll-like receptors”) whose job it is to recognize invading pathogens. When they do so, one effect is for them to increase the production of vitamin D (or more specifically, its active form 1,25D3) by another cell of the immune system (“monocytes”) - and this leads to more cathelicidin being produced.

    There are also more direct mechanisms, shown in other studies. What this one shows is that when, following a wound, there is an increase of cathelicidin, this process is dependent on/involves vitamin D as one of its steps. And it describes the precise mechanisms of this process. So its just filling out that link between vitamin D and cathelicidin.

    Kallikrein Expression and Cathelicidin Processing Are Independently Controlled in Keratinocytes by Calcium, Vitamin D(3), and Retinoic Acid

    We only have the abstract, here, which is a great shame.

    The basic message is this. Cathelicidin expression is not a simply on/off affair. It is more complex - the expression can be modulated in all sorts of ways. And three particular agents/biological components in particular, have been found to play an important part in this control: calcium, retinoic acid (the biologically effective form of vitamin A), and vitamin D3. They alter the expression of cathelicidin, by altering the expression of kallikreins. They are each one part of a complex control mechanism, each with different specific effects, just as, say, applying different tools to different parts of an engine, will tune it in different ways.

    (2010) Control of cutaneous antimicrobial peptides by vitamin D3

    Vitamin D is emerging as a major player, in the regulation of the expression of cathelicidin. Although many other elements have a role in the mechanism, D3 seems to be assuming the mantle as a sort of 'master regulator'. Point is, it therefore opens up the possibility that, if you could manipulate D3, you'd have some control over the expression of cathelicidin...and that's what we want, obviously.

    But the precise mechanisms, and how it all fits together, isn't known yet. This paper just looks like a review paper, saying where knowledge currently is at.

    * * * * *


    (1998) Apolipoprotein A-I Binds and Inhibits the Human Antibacterial/Cytotoxic Peptide LL-37

    This is not likely to be of any relevance to us, but just provides some background filling. It is observed that, although cathelicidin is present in the blood, its antibacterial activity, and its activity on the outside of cells, is inhibited there. This study identifies the agent in the blood responsible for this inhibition – apolipoprotein A-I.
    The slight relevance of this is that obviously, if Gallo's theory is true then we want to downregulate cathelicidin. However, I don't think we'd be doing it with apolipoprotein. So, as said, this is just background.

    * * * * *


    Nafamostat mesylate is a specifically designed protease inhibitor, and is the compound being used in trials underway by DermaZaide.

    (2003) Nafamostat Mesilate Is an Extremely Potent Inhibitor of Human Tryptase

    There are lots of articles about Nafamostat, which has been used as a long time clinically in pancreatitis, though not in the skin. This article reports that it is an effective inhibitor of tryptase (as well as mentioning its trypsin-inhibiting ability. Not sure about the difference here). It also gives details about the mechanisms

    (2004) Improvement in Wound Healing by Epidermal Growth Factor (EGF) Ointment. I. Effect of Nafamostat, Gabexate, or Gelatin on Stabilization and Efficacy of EGF

    Two reasons why this is interesting. First, if Nafamostat is being safely applied to open wounds, it shows that its pretty benign, and so could be safely used on the skin. Second, it evidences how Nafamostat can inhibit proteases in the skin – proteases will slow down wound repair by degrading the structural building blocks of the repair process.

    (2008) Dramatic Improvement of Subcutaneous Insulin Resistance with Nafamostat Ointment Treatment

    The reason this is interesting is just because it shows that topically applied Nafamostat does get into/through the skin. That isn't the end of the matter, because it might break down too soon to do any good, go right through without staying in the right place, and so on. But its the first hurdle cleared.

    Abstract only

    (1999) FUT-175 inhibits the production of IL-6 and IL-8 in human monocytes

    Nafamostat is also known as FUT-175. Monocytes are important parts of the immune system, and IL-6 and IL-8 are important inflammatory mediators. IL-8, in particular, is noted to be upregulated by cathelicidins, although this may be through a different pathway

    * * * * *


    (1990) Location of the protease-inhibitory region of secretory leukocyte protease inhibitor

    Inhibitors depend on their shape to work – just like a lock and key, an inhibitor will somehow 'fit into' kallikrein, or vice versa, to stop it working. This study examines the structure of SLPI, to see which bits of it are responsible for its inhibitory effects against various trypsin-based proteases

    (2005) Anti-Inflammatory and Antimicrobial Roles of Secretory Leukocyte Protease Inhibitor

    Again, not likely to be of much relevance. This review gives details of a certain protease inhibitor – sectretory leukocyte protease inhibitor/antileukoproteinase. Nothing is said about it inhibiting kallikrein, and indeed it seems that most of the areas where it is expressed are other than the skin (but see below). But it does inhibit the activity of various trypsin-based proteases, which is what kallikrein 5 is. So, maybe one can draw some background information from this kind of thing.

    Abstracts only

    (1998 Abstract) Antileukoprotease in Human Skin: An Antibiotic Peptide Constitutively Produced by Keratinocytes

    Antileukoproteinase is in the skin. Combined with the above study about its trypsin-type inhibiting functions, it looks possible that it could inhibit kallikrein.

    * * * * *



    (1997) Soybean Bowman–Birk Protease Inhibitor Is a Highly Effective Inhibitor of Human Mast Cell Chymase

    Forget the “Bowman-Birk” name, we're still talking about Soy protease inhibitor. This mentions the fact that it is effective against trypsin-based and chymotrypsin-based proteases, and establishes that it is also effective against chymase, which is a protease released by mast cells.

    (2004) Inhibitory effect of topical applications of nondenatured soymilk on the formation and growth of UVB-induced skin tumors

    Its just interesting to observe that topical soymilk has been used – this is otherwise of no particular relevance.

    * * * * *

    Tetracycline antibiotics

    Gallo frequently says, in his papers, that tetracyclines inhibit kallikreins, as part of the evidence for the wider theory. I've had difficulty locating studies showing this, but there is some material on the tetracyclines' activity in some of the processes in which cathelicidin-initiated inflammation is involved.


    (2009) Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocyte

    Tetracyclines inhibit IL-8. This is an inflammatory mediator that is upregulated by cathelicidin. However, this study focuses on the IL-8 produced via a specific pathway. I'm not sure that it is the same as that through which cathelicidin acts.

    (2009) A Dermatology Foundation newsletter. (Page 11)

    To be found at:

    There is a brief overview of Gallo's theory, but the significant thing here is the excellent graph supplied, which displays very clearly the effect that minocycline (a tetracycline antibiotic) has on KLK5 - i.e., the kallikrein which plays the chief role in activating the inflammatory form of cathelicidin.

    * * * * *


    A somewhat wild (because completely speculative) theory I have is that since tetracyclines bind metal ions (indeed, it seems that they must do this before they can work) that therefore, possibly, over time, tetracyclines bind Zinc ions in the skin, making them less available for the inhibition of kallikrein. They may even scavenge them from off the backs of kallikreins.

    * * * * *

    Skin barrier, desquammation etc

    By Gallo's theory, rosaceans are thought to have high levels of kallikreins (#5 and #7 specifically). These kallikreins are centrally involved in the process whereby old dead skin is continually shed off (“desquammation”). They break/degrade/eat the little ties or links that hold together the dead skin cells at the outer layer of the skin (the “stratum corneum”). So, if we have high levels of the kallikreins, its natural to assume that we would have excessive desquammation.

    I think many rosaceans do have this, but perhaps don't recognize it because it is not
    obvious. Excessive desquammation would mean the skin barrier is poor. That would lead to symptoms like: dry skin (poor skin barrier means moisture isn't retained), sensitivity to irritants (because they're not kept out), 'sensitive skin' (because it doesn't take much for things to get where they shouldn't), possibly greater susceptibility to invading pathogens, and so manifestation of other diseases, and also, possibly flaky or scaly skin. It will depend on how serious things are, what particular symptoms are

    Anyway, so this means that studies relating to how kallikreins take part in desquammation are of interest.

    (2001) Refined Characterization of Corneodesmosin Proteolysis during Terminal Differentiation of Human Epidermis and Its Relationship to Desquamation

    Corneodesmosin helps hold together skin cells of the outer layer, and the kallikreins slowly snip it, smaller and smaller, until it can no longer do this. This process is supposed to happen in a regulated manner, but rosaceans' extra kallikrein may mean it happens too quickly, and therefore our skin barrier is deficient.
    This study gets into the details of how corneodesmosin is proteolysed. Also some good background on the other adhesive structures between the outer skin cells.

    (2004) Degradation of Corneodesmosome Proteins by Two Serine Proteases of the Kallikrein Family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7

    This study is the chief reference point for saying that the adhesive structures holding the outer layer skin cells together are degraded by kallikreins 5 and 7. It goes into the details of how this happens. Incidentally, they also mention various other proteases which may have a role to play in desquammation, such as various cathepsins, whose activity has yet to be fully elucidated.
    The paper contains this nice schematic diagram of the desquammatory process:

    (2004) Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice
    This study shows that corneodesmosomes are necessary to the cohesion of the stratum corneum, by deleting the gene that codes for an inhibitor of kallikreins – the elements responsible for degrading them. Therefore the kallikreins run amok, and the poor mice have no skin barrier. In fact, this reproduces the symptoms of a human skin disease called Netherton's syndrome, in which, similarly, this gene is defective.
    One thing to think about is this. In Gallo's theory, rosaceans are said to have too much kallikrein. It would seem strange, then, that our symptoms are not more like that of Netherton's syndrome.

    (2008) Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology
    The structures that hold together the cells at the outer layer of the skin are called “corneodesmosomes”. These are themselves made up of several different components. This study examines the role of one of these – corneodesmosin – to establish how importance it is in maintaining integrity. Mice with the gene for this component deleted have a very disrupted barrier.
    Degradation of these components by the kallikreins leads to desquammation – possibly too much, in the case of rosacea.
    Corneodesmosin also seems to play a role in the hair follicle. I've noticed that a few rosaceans report a bit of extra hair loss (of things like eyebrows), so this could be a factor.

    Abstract only

    (1993) The role of proteases in stratum corneum: involvement in stratum corneum desquamation

    Shows that trypsin-like and chymotrypsin-like proteases (which is what kallikrein 5 and 7 are, respectively) are involved in desquammation.

    (1998) Stratum corneum, corneodesmosomes and ex vivo percutaneous penetration.

    Key: Light-grey ovals are proteases; dark grey circles with dotted lines are inhibitors; black boxes are the components of corneodesmosomes. Question marks are indicating that they don't know what happens to the bit that comes off the kallikreins after they are activated.

    This is a rather interesting abstract, since it gives an idea of how kallikreins find their way to corneodesmosomes, to then proteolyse them. The process seems to be that, as the outer layer of the skin spontaneously organises itself, it separates into hydrophilic (water-loving) and hydrophobic (water-hating) regions. Corneodesmosomes occupy the former region, and so do kallikreins.

    (2003) Structural and ultrastructural data on human cutaneous lipids
    Covers exactly the same process as the 1998 abstract (“Stratum corneum, corneodesmosomes...”) except from the point of view of lipids, which are barrier-forming components of the outer-layer.
    Last edited by TheMediumDog; 27 March 2010, 09:09 AM.


    • #3
      Thanks so much for that!!! Totally interesting about the cause of our flakey skin!

      Now I'm confused because I was on doxycycline and didn't have improvement so does that still mean I have cathelicidin/kallrein (sp)?

      So now the question is... How do we fix this? Can't kill it all off cause we need it too correct?


      • #4
        I think that antibiotics block something a little further down the line. So, you still have high levels of kallikrein/cathelicidin, but they don't have their full inflammatory effect because the antibiotics are stopping them from initiating it. For the inflammation to happen, the cathelicidin has to start a chain of, like, maybe 10 further processes. So, at some point in this chain, the antibiotics intervene, and break it. But I think this means you still end up with high kallikrein/cathelicidin levels.

        Yeah, the question is how do we fix it. But I don't think Gallo's theory can tell us that because I don't think it tells us the cause (as Jenny and others have pointed out to me). All it says is that 'this and this is part of the mechanism by which inflammation happens in rosacea'. But why do we have high kallikrein/cathelicidin? I think Gallo doesn't have any real answer to that question.


        • #5
          Wow, MediumDog, thank you SO MUCH for your incredible dedication in making all that information available and understandable. I am so impressed!
          Permanent redness, p&p's
          Ivomec, Avene anti-redness cream


          • #6
            this is great, am going to spend some later taking this all in


            • #7
              There must be a way around paying for articles. Paying for things is very irritating.

              Truly, excellent stuff. Though bear in mind while you were doing that I was watching Come Dine With Me in my underpants. So you have to ask, is it all worth it?


              • #8
                If you do want the article, I can email it. I'm loathe to post it up because Nature might come and make us pay for copyright infringement.


                • #9
                  Kind of you to offer, but I was thinking of this one

                  (2009) Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases

                  and not Gallo's. Thanks anyway.


                  • #10

                    many thanks for all you time and effort you are putting in this!



                    • #11
                      Originally posted by GJ View Post
                      Though bear in mind while you were doing that I was watching Come Dine With Me in my underpants. So you have to ask, is it all worth it?
                      Yeah not having a TV can really get you into some mischief. Who knows where it will all end up. There'll probably be tears.


                      • #12
                        Originally posted by EK1 View Post
                        Totally interesting about the cause of our flakey skin!
                        You know what, I think that, at least in my case, what is going on is that there is an imbalance of bacteria on the skin (due, in my case, to antibiotics). And therefore, there's some bacteria/other microorganism around which shouldn't be there, and the skin is desperately shedding in order to try and get rid of it (because constantly turning over new skin is a defence mechanism).

                        Either that, or some pathogenic bacteria is producing an irritant which is making the skin over-shed. And doing this, because this makes a nice home for it - lots of dead skin it can eat or whatever.

                        But so either way, I reckon the cause of the flakiness may be located with micro-organisms. All the stuff about kallikrein etc just gives you some of the mechanisms.

                        I think its got to be something like this, because not many rosaceans have very flaky skin, even if their rosacea is bad. So its got to be something more individual, like a bacteria.


                        • #13
                          Thanks so much Alex. Really great job.

                          Originally Posted by GJ
                          Though bear in mind while you were doing that I was watching Come Dine With Me in my underpants. So you have to ask, is it all worth it?
                          Sounds like an intriguing show.
                          Sadly, I don't think we get it here


                          • #14
                            Originally posted by TheMediumDog View Post
                            Yeah not having a TV can really get you into some mischief.

                            I'm sorry. I didn't know things were quite that bad. We are all here for you, MD. I urge you to speak to a friend or a professional. Stay strong, brother.

                            You would enjoy it, Melissa. Not sure how well it would work for the rest of your countrymen though.
                            Last edited by GJ; 19 September 2009, 05:10 PM.


                            • #15
                              Thanks Alex for taking time out to do this - it made it easier to understand.

                              Originally posted by TheMediumDog View Post
                              All it says is that 'this and this is part of the mechanism by which inflammation happens in rosacea'. But why do we have high kallikrein/cathelicidin? I think Gallo doesn't have any real answer to that question.
                              I don't think he has either and he could be barking up the wrong tree. I hope I'm wrong because the NRS have directed a considerable amount of money his way so that this research can continue.

                              There was talk about seeing if Gallo would be interested in doing a Q&A session on here about rosacea in general and his research?

                              My question would be "Some experts consider that rosacea is a self-limiting condition and does eventually go into remission. There is evidence of this happening and sometimes it can be spontaneous - why do you think is and how do you link this occurrence into your theories?"