Immunity, history and understanding

well a warm welcome to this talk and regular viewers to the channel will be no stranger to professor robert clancy from sydney in australia uh consultant uh physician uh professor of pathology uh author of too many articles to enumerate and and of course uh an immunologist now well welcome robert thank you for coming back uh great pleasure john thank you so we've talked about the the covert vaccines before i don't want to dwell on that but but i think we decided that one of the main problems with that was it wasn't really taking into account the the the host parasite relationship and and the way that this works in the respiratory compartment as well as the systemic compartment is that a fair summary robert i think that's that's a good summary john what we decided was that when people looked at covet it was a very confusing complicated issue and much of the advice and discussion it doesn't seem to take into account uh a modern understanding of exactly the immunology and the compartmentalization of immunology and so we decided to look at immunology from a layered historic context to try to decode it if you like to simplify and we started off by asking the question what is the host post host parasite relationship and it's what infection is all about uh for example there's a lot in the news about uh meningococcal disease at the moment and we know that many people listening here will have some of that organism in their nasopharynx stuck in their their throat and yet they're not sick and they're not going to get sick and yet maybe one in a thousand of those people can get a life-threatening infection uh which uh is very serious very rapid and so we have this idea that the illness that you see is the outcome of the relationship between on one hand the pathogen the bacteria or the virus and on the other hand the way in which the body handles that which is the immune mediated relationship and so we we're going to talk a lot about what a host parasite relationship is and particularly from the immunological viewpoint because if you get covert for example the the outcome of that disease is determined by the way in which that virus is handled is it contained does it get away from where it should be and understanding those basic mechanisms is essential in making the decisions on how you approach management be it vaccines oral therapy or isolating individuals because they may or may not be excreting the virus so all of those things are tied up with this immunological concept of relationship um and i guess this is true of any disease robert that the symptoms that someone actually suffers from of a combination of the infection itself the parasite and the way that the body the host is is reacting to this is combating this is suffering from the effects of this infection yes that's that's absolutely right john that if we look at something like oh take covert because it's a very topical most of the problems that you get from covert is not due to the virus itself but it's the virus being in the wrong place and having an exaggerated inappropriate body's response causing if you like the viral pneumonia but what we found was that's how we thought about it right at the beginning and then we found that the virus itself has a level of intrinsic toxicity it has what's known as the spike protein and the spike protein i think was a big surprise because that's the protein that we incorporate in basically all the existing uh vaccines the spike protein itself can have a lot of damaging effect and so as with most post-parasite relationships the outcome the symptoms the signs the degree of illness is the combination of the way in which the body is responding and any intrinsic toxicity that that pathogen virus bacteria may have that makes perfect sense robert thank you now we want to go back and look at the historical development of this because we just decided that immunity is such a complicated subject just to go sort of straight into the cutting edge of it wouldn't make too much sense and we have to understand the way that the thinking is developed and this isn't purely for historical interest although it is historically interesting but it's really to facilitate a deeper understanding of the nature of the subject and how the subject has been so misunderstood uh by many people who are even professionals in the field um over the past couple of years so going back to let's go back to the 19th century pre-1880 um we had this idea that disease was caught by caused by miasma and imbalance of the humors which which are lovely ideas so we still say to each other are you in good humor today or uh you're full of bile or something like that which which goes back to these ideas yeah the the melanoma the the black bile i'm often melancholic it goes back to these so the first idea was was miasma what was the thinking that what was miasma you know it's very interesting for 2 000 years uh the idea of illness was some outside fact of some toxic miasma would change a balance between four humans and this of course was consistent with the way the greeks saw the world the universe everything was for the earth the fire water uh and when it came to humans it was the black bar the white bile blood and air and all of a sudden um the whole of medicine was identified in a disturbance of balance which is quite interesting because as we move on to immunology you'll see we still talk about a lot of the the balance and outcomes now the great change that came was when louis pasteur in paris uh identified bacteria and what this did is and it was probably the biggest change ever in medicine it gave specificity to medicine because prior to pasteur identifying particular bacteria with particular diseases everything was non-specific this non-specific change imbalance and so all of a sudden we had a particular type of pneumonia caused by bacteria number one or bacteria number two or bacteria number three and it was a simple jump from there for the people in pasteur's laboratory and robert [ __ ] who was the german competitor of pastor no love lost between them and the franco-prussian war about the same time uh they they spent their lives in their laboratory spent all their lives running around the world to find a new infection that they could find a new bacteria from but at the same time they found that every time they found a bacteria causing infection one or two they'd find in the blood some specific neutralizing factor which ultimately became known as antibodies and so antibodies have been around since uh the late eighteen hundreds as the body's response to a specific bacteria so we're starting to get this idea then of host parasite relationship in the era of specificity but this is sort of about 1880s we're talking here when this work was really getting going i'm guessing that's right and and things move so quickly john uh by 1880 uh pasteur had set up his anthrax clinic where he was treating people who or animals mainly who were getting anthrax was a huge problem in those days and the a very lethal problem it was big problem in new south wales we called it cumberland disease because until pastor sent his nephew out to australia to fix up our rabbit problem and he diagnosed the first anthrax in australia but this was the first vaccine and he moved on to a vaccine for rabies which of course is a viral illness uh and his bacteria yes the anthrax was a bacteria rabies was a virus but he had no idea of course what a virus was he saw them all as some sort of bacteria and robert [ __ ] was doing the same and i've just been writing something today on the bubonic plague that we had here in 1900 and uh that was a huge battle between a [ __ ] acolyte and a pasteur acolyte that rushed across to asia to work out what was causing uh the black death that had appeared in its new waveform so we had antibodies and then very quickly people worked out that they could take the parts of the bacteria or make the bacteria not causing illness and inject it and stimulate the protective antibody without getting the disease so this was the beginning of immunology the beginning of immunity and so we went from the host parasite relationship which of course on one hand could be quite asymptomatic or on the other hand it could be a dramatic overwhelming sepsis with death following very quickly so you could convert someone into having if you like a symptomatic infection getting the immunity without the disease and that was the basis of the very early uh vaccines that developed and at the same time they could inject horses with the bacteria that kill the bacteria first and they would take this the blood and make the antibodies from the serum or didn't actually they use the whole of serum to actually inject the serum into patients who were getting say pneumococcal pneumonia and suddenly they were able to save patients by what they called passive immunization so we had active immunization where you made a vaccine by taking a a product of a dead bacteria or a toxin produced by the bacteria tetanus or diphtheria or you would actually put the bacteria and grow it and grow it and grow it until it ran out of energy and could no longer cause disease but it still had its antigens the part of its body that would allow it to stimulate an antibody and so you could take that inactivated if that that fatigue bacteria and and put it into people and that would be a very effective safe vaccine so interesting isn't it so the people before this recognized that there was a disease that kind of presented like that and a disease that presented like this in a disease that presented in another way but then when they went and looked they found the specific etiological organisms for that disease a particular organism causing a particular disease yeah and that and then it's really so yep yeah yes yes it's complete revolution but then it's so simple in essence you just take the organism that's causing the disease kill it yeah inject it in a dead form and and the body recognizes that and actively makes its own immunity which is the active immunities it changed changed medicine changed life yeah that was and that that that's what the chinese vaccine was wasn't it it was just just an attenuated virus it's just well it's an inactive by the virus and in fact it makes a lot of sense i mean the flu vaccine that we've been using uh for 40 50 years was was just a inactivated flu virus and then to make it less toxic they broke it up and just pulled out the bits that were specifically stimulating a protective antibody and so vaccinology has been a fairly crude science when you think about it it's about making the bacteria or the virus unable to cause disease but still able to stimulate protection and you brew these things up it's almost analogous to making beer or something isn't it it's that kind of well that's how pastel made his name and his fortune uh he found that uh when the beer went off or in the wine yeah which was more important in france um it was due to fermentation by the wrong bacteria and so uh and of course he found that tuberculosis from milk was the same and he developed pasteurization from louis pasteur by boiling the milk killing the bacteria and making the milk safe to drink so really i think we could call this please no i was just going to say that everyone hopped onto the antibody bandwagon this was and i think this is very good way to sort of get to understand immunology because this is really what immunology is all about but a couple of things occurred within literally four or five years the first was that uh the antibodies um sometimes they would inject all sorts of uh crude antigens into a dog or something like that and in trying to protect it against putting in a live bacteria or virus although they didn't know what a virus was in those days and they found that instead of getting protection sometimes they got incredible inflammatory response this is very important concept because this was the introduction of the idea of hypersensitivity which basically says that sometimes antibodies can be protective sometimes if they're inappropriate or they're mixing up with the wrong sort of collateral agents they can cause damage and this was called hypersensitivity and it introduced us to a very very important component of immunology and that is that the antibodies really can't do everything on their own and if you think about it there are at least five or ten thousand different patterns on bacteria and viruses in the world and we just don't have enough cells to make hundreds and thousands of cells capable of marshalling an army of specificity to kill those bacteria or viruses so the body's very clever it it it adopted what had been around since the earthworm and very primitive organisms called the innate immune system and this is a system of protection that predates both our knowledge and also humans going way back to the invertebrate kingdom it predates that to coming up with a system that could protect against infection without having antibodies or specificity now those processes are what we now know as the innate or non-specific immunity and they look like foot soldiers we can think of the antibody as a general of an army and what he does he says okay army i want you to attack and so that army will attack that city or this city whatever city that the specific specificity in the general decides needs to be attacked and if you get that process of connection wrong those soldiers just fire their guns anywhere it's like a hand grenade and it'll go off and it'll kill anything that's around and if you don't target that innate system very accurately that hand grenade will destroy part of your body and you know i can remember as a student john i couldn't i mean all this stuff was not clear and i i remember going up to the professor and saying look how on earth can we have protection prophylaxis and damage hypersensitivity or anaphylaxis how can we have both of these being mediated by the sometimes the same antibody and of course the answer is that it all depends on how connected and how controlled the uh the specific antibody and later we'll talk about t cells but now we're talking just about antibody can connect with this foot soldiers running around in the bloodstream and if you don't get it right and you get an overactivity then you actually get inflammation and damage inflammation is just a response to injury it's uh it's can be protective or it can be damaging depending how well it's controlled but it's the non-specificity of this uh cells and humeral factors and initially it was thought that the factors were in the serum or the non-cell part of blood and the the term was given eventually as complement because it complemented the antibodies so you had antibodies and complement which turned out to be a very complicated series of enzymes and proteins but they would have amplification systems built in to achieve the outcome in a time frame and time frame becomes incredibly important because if you've got bacteria and virus dividing you have to control that infection quickly and so uh that's why the activation of this innate system and its control is so important you set that hand grenade off just to kill the bacteria but i think the idea of hypersensitivity is very important because when we come to covert we'll find that the pneumonia that you get in the as the virus gets into the gas exchange part of the lung is due to a hypersensitivity due to the igg antibody the antibody recruiting inappropriately and excessive these innate immune mechanisms it's incredible so basically it's a race the organism is is frantically reproducing if the organism reproduces enough it will kill us so we have to activate our responses quickly and if we have to activate our responses quickly that means these responses have to be potent and if we take that non-specific mechanism like complement for example it can make these perforated proteins can't it that can actually lead to cell death which is good in the right circumstances but if you have too much of that if it's killing cells inappropriately we're going to get an inflammatory response so it must be precisely moderated just to attack the the attacking organism and not attack anything else and not cause other inflammatory mechanisms because inflammation can be good but our inflammation can also be deadlier as you mentioned if it's in there exactly i i think that's that's a really important point but the inflammation is just a term we use for response we tend to get it wrong by thinking it's damaging you know you've got a hot red toe in gout that's an inflamed toe uh in fact if it does its job properly then it does it without getting hot and red and inflamed and involves these non-specific cells and humeral or soluble factors in the serum of blood or the plasma of blood so really what we're learning from this is that we have these two things we have the innate response and the specifics response the specific response is a specific organism a bacteria or a virus generating a specific like reciprocal antibody that's specific only against that organism but we can also get the activation of this non-specific response like the complement and uh and and later on we would learn that the the uh the innate response will probably include the natural killer cells that can kill a wide variety of cells um the these these are acting in tandem and they need to act quickly so so so that the the the the attacks what was found with this hypersensitivity uh reaction was that it was time dependent uh that if you for example did a skin test in somebody uh you could get an inflammatory rare or a positive um swelling and redness very quickly within a minute or it could occur after several hours or sometimes after several days and so very early in historically it was recognized that there were three forms of hypersensitivity or inflammation causing damage and we'll jump forward and cheat a little bit because uh it was found that the first type the very quick one that occurred within minutes is caused by a particular antibody that wasn't really discovered until the about the 1960s by a japanese couple and this is the uh i ige antibody because most of you will know about the igg antibody because that's the one that we're going to talk about causing uh covert but the ige antibody is the one that causes allergies hay fever asthma eczema and this antibody binds to cells which release factors like histamine and you're all familiar with histamine antihistamines uh and and that was the immediate the immediate type of inflammatory response and that's why when you go to the allergist he does skin tests a bit of house dust mite bit of grass weed to see which type of specif specifically what you're allergic to because he may want to then desensitize you by injections and turn off that process the second one was due to hours and that was caused by igg antibody binding to complement which we just talked about causing a swelling and redness the third one was tricky because they couldn't find anything in the blood serum or the blood plasma that's the non-cell part of blood that could mediate this by transferring to other people and what they found was that it must be a cell rather than an antibody and so the idea that there were more complicated processes involved in immunology involving cells was seeded very early and this of course uh was the work done by robert [ __ ] in berlin and became a key part of our understanding of tuberculosis and the mantu test which many of you would have had because that's the one you come back to the doctor two days later to see if you've got a lump that's the t cell mediated or the delay what was called delay type hypersensitivity so we have protection we have hypersensitivity and damage we have immediate intermediate and delayed caused by antibodies or cells it's incredible yeah and and and the cells turned out to be t cells which we'll we'll come across later which is um we better not cheat too much no no some minute some minutes ago though i said there were two two things that were found the first was this idea of damage as well as protection the second was that it came straight after the third of the great thinkers in this period time period a man called paul ehrlich who was also german as was robert [ __ ] and paul ehrlich said ah this wonderful observation by pasteur only occurs against not-self something outside of the body you could never have a reaction against yourself the very next year another german landsteiner who's responsible for sorting out blood groups he found that in a poor little child with congenital syphilis uh auto antibody was there and anybody was killing his own red cells and so within 12 months of ehrlich saying a term known as horror autotoxicus you can't possibly have an autoreacting toxin anybody landsteiner had shown yes you can and that of course was the beginning of autoimmunity uh which is a very large part of what i do from a clinical viewpoint so this is 1920s robert i'm guessing now no no this this no though this was this was earlier this was uh before early in 10 19 years very quickly well okay right right yeah so just to clarify we've got um extrinsic um antigens which are the viruses and bacteria yes and we've got auto antigens which which are part of ourselves is that is that exactly basically is that too simple no no it's exactly and both of those act as antigens which can stimulate the production of antibodies exactly and if we jump forward a little bit uh we'll find that we there's an organ up here behind the breast bone called the thymus and the thymus has the job before we're born of sorting out whether your cells are autoreactive or whether they can be there to defend yourself against bacteria and viruses and that it basically the thymus has this regulatory uh function of getting rid of the autoreactive cells and letting only the non-autoreactive cells get into your circulation and into postnatal life now it's not quite as simple as that as we'll find out but that was that's more or less the broad idea incredible yeah so it's possible to have auto anti-auto antibodies that for example destroy the beta cells in the pancreatic ions of langerhan nuts exactly exactly juvenile type 1 diabetes is an autoimmune disease where the beta cells that make insulin in the pancreas are destroyed by an auto antibody um we have uh many but the probably the commonest one would be systemic lupus erythematosus or lupus which many people will have heard of where you have auto antibodies against parts of the broken down cell nuclei uh causing complexes which cause all types of problems uh but i guess we'll we'll get on to that a little later so again again we get the idea that antibodies can protect or cause damage exactly exactly and and yeah when we think about it within 20 years of us going from uh the idea of for humors and balance and miasma in 20 25 years we've gone to the basic tenets of immunology as we understand them today we we have um antibody system coming from what we now know as b lymphocytes we know that there's some cells we don't know much about them we know that these antibodies can be protective we know that they can react in a allergic or hypersensitivity way and cause damage we know that under the wrong circumstances they can actually direct against yourself so you actually have uh the the pattern of immunological diseases starting to be fairly well understood in many ways uh within 20-25 years of the whole idea of specificity uh being born yes all this we've talked about here is is completely recognizable to to uh um for example you'd recognize this reading a modern textbook and we're talking about basically getting on for 120 years ago that this these ideas have been around for i think the problem i think john has been that that we immunologists tend to use mouse names uh we talk about the complexities and uh as we progress we'll realize that when i started an interest in immunology there was still this big black box this whole concept of how the molecules and cells become interactive and of course that's a great interest to to people like myself but it takes away from the simplicity of understanding exactly what's happening now i i think by the time we got to 1920 um world war one wars have terrible outcomes and but sometimes great discoveries um i just want to introduce uh the concept which you really talked about right at the beginning and that is the compartments because up to now everyone was thinking of what was happening in the bloodstream systemic we call that the systemic immune response occurring inside the body operating very quickly because it has to cope over very short time frames but there was an amazing man also out of the pasteur institute uh called bes wrecker now bezreckka uh it was a very famous immunology at the time and he realized that that with some infections for example dysentery and typhoid fever which were particularly involving the the gut he was finding some antibodies in the stools of patients before he saw them in the blood and he said well that's interesting maybe what's going on in the the gut is particularly relevant to an infection of the gut maybe there are different compartments and to kind of very long an important story short he actually immunized soldiers in world war one with killed dysentery bacteria and showed that you could protect against dysentery to some extent by immunizing by the mouth to actually activate what he saw as some form of regional immune system didn't understand the details but he understood that there was a separation that becomes really critical when we look at covert because covert is an infection of a mucosal compartment it's an infection of the lining of the breathing tubes in the lung and the upper airways it's only when it gets out of those breathing tubes that it causes a lot of mischief fascinating character alexandria uh beretzka thank you he was a medical officer a medical officer in verdun that's right he was born he was born in uh odessa where what country is that uh i know he's born you cried he's he's yeah that's you yeah yeah well there you are but he was working with the french military verdun of course people people know this you'll know this it was an appalling killing ground in the first world war the the the french army was stuck there for oh i don't know a year at least in the trenches and you notice men passing uh getting really bad gastroenteritis with mucus and blood that's right that's right i think this turned out to be shigella robert didn't know yes that's right shigella dysentery and he he would take the shigella grow it up inactivate it so it wasn't toxic and feed it to uh to the soldiers uh he had a very illustrious career and uh he was he actually ran the pastor institute for a period of time uh quite an amazing man not just in in mucosal immunology but and just if you give me just 20 seconds so it brings me to please um i i had a very important person in my life died last week it was john boehner stop and i know many people many people watching this his family and friends i know supporters of yours john john was the father of modern mucosal immunology in the sense that there's communicating networks between the different mucosal surfaces he was also my mentor my guide and my one of my very best friends and uh sadly at the late 80s he died suddenly in the street but i just want to pay respect to him because john was the person who first showed that cells would migrate from one body surface to another and we'll get on to how important that is in understanding protection of the airways and protection against covert so uh john it was very much working on on the develop developing the work of alexandre uh he was he introduced me to uh alexandra uh bezrecka uh in fact uh he had a copy of his his book and uh he bezrika was uh john benestock's uh a great hero indeed i really love that this is such a simple idea the the that alexandria barretska had it he looked at the stores that these soldiers were passing he found there was antibodies in there we realized that these antibodies must have come from the gaster interspinal tract because they were therefore we postulated this idea of gastrointestinal immunity they weren't in the blood therefore he gave attenuated or dead bacteria stimulating the same antibodies generating mucosal level protection against together and and in doing so saved unknown tens of thousands of lives that's right but by that simple sequential thinking doing that right so rather than injecting vaccines that has been done before you just simply gave them orally to work in a particular compartment yeah and i think that this is such an important principle uh if we take influenza or covert 19 these are primarily mucosal infections and so if we inject the antigens they won't have any impact on the behavior of those organisms in the airways and that's why the vaccines are very effective at preventing people dying or becoming extremely unwell once that bug gets into the alveolus where the gases are exchanged because that's where the igg and systemic immunity can operate but it won't impact on the division in the broncos and the broncos of course is the conducting uh passages and that's why the vaccine has very little impact on preventing spread of the infection so you can be vaccinated and maybe just get a cough and a bit of a wheeze but uh you're still going to be invective in a community maybe not quite as much but certainly infective uh whereas it'll protect you from the virus going down and meeting a pro-inflammatory antibody like igg which could create so much damage and i suspect andre baretzka and your friend john would have both realized this straight away absolutely absolutely unfortunately they're a part of a very small group indeed but i mean we learned this from nature itself robert i mean colostrum that mother produces in the first day or two of breastfeeding yeah absolutely and for animals that line the gastrointestinal tract of the child so sorry what you say animals what no a lot of animals really depend on the colostrum from that milk from their their mother um and humans yeah and of course we can't recommend it highly enough for human babies either that's absolutely i mean there are a lot of reasons why uh breastfeeding is absolutely critical but um and this the breast is part of this common mucosal system and there's a transmission of ideas between these surfaces and you have a singular aggregated lymphoid tissue in the gut is actually the main factory for the antibodies and the antibody is a very different type of antibody it doesn't fix complement in the same way that igg does so you don't get this pro-inflammatory effect which of course you don't want at mucosal surfaces so there are great differences between these compartments and of course you implied this and applied this in one of your inventions which was basically the oral vaccine for recurrence of chronic obstructive pulmonary disease just sketch that out briefly for us robert if you don't mind um well i was very lucky i worked with john bienistock for five years and my first job was just killing the rabbits he thought i was an australian and so he gave me the job of killing the rabbits because he thought all australians hated rabbits but um i wasn't as bad as my canadian colleague who i work with would take them home and eat them um but uh what he did very humanely robert oh very good very humane i quite quite like rabbits uh but the what what i did when i went back to australia was like i thought well look does this work in humans and so i set up model systems uh and i particularly in chronic bronchitis in in people who were smokers and we were able to show that uh the system worked very effectively in humans and um but it wasn't a hundred percent and that we could make that system of protection work far better if we actually took the main bacteria from the airways did what pasteur did and killed those bacteria fed them in large amounts protected them from destruction by acid in the stomach and we've got this surge of protective cells and antibodies that would protect the airways in animals and in humans against against infections and we were able to by doing this people with emphysema and chronic airways disease who dread the thought of getting a virus infection because it so quickly goes to their chest and they get serious uh problems because they've got compromised lung function we were able to reduce admission to hospital by 50 in those patients with chronic uh production of sputum and cough so simply by making a normal natural process work in an optimal way so the understanding the basic immunology really does have some some practical outcomes don't ask me if you weren't if you remember we could talk about that but if you've ever worked in healthcare you'll realize the impact of what robert has just said if we could reduce admissions of copd or exacerbation of chronic copd by 50 then we could probably take most of our afternoons off because it's a huge amount of work for the for the health for the health services that these people come in and a huge amount of suffering why the heck isn't this being done robin sorry what what could you ask the question why isn't this being done why isn't your vaccine invention being used um i uh it's a long long story john um it's the i'm not a commercial person i'm not very good commercial person uh and uh it's it's over many years we've actually developed this to a fine point but uh um maybe it'll happen in the not too distant future i'll talk to you i think we'll leave on that cryptic note we'll leave it on that cryptic note which i'm very much looking forward to but when it when and if this is operationalized if we could reduce admissions of these patients by 50 that would be huge because they're good i mean our yeah you know we're looking forward to something on that just out of interest robert did you use um a sort of a combination of bacteria and viruses from mucosal secretions was it that's a very very good question uh in europe anyone listening here in europe will know of a number of products uh and they're very interesting products they're lots of different bacteria in small amounts and this comes out of again world war just after world war one uh when influenza uh the spanish flew the flu that killed 50 to 100 million people when that appeared a lot of people were young people who were dying and they would not they would get flu but they would die from a bacterial infection of the lungs mainly staphylococcal pneumonia and a number of people in both britain and australia and various parts of america started putting together because the idea was that bacteria bacteria the viruses weren't known at this stage bacteria caused all these infections they didn't know what bacteria so they just went to people's airways and grow grew up every bacteria that they could find put them together and injected them now the amazing thing is that 50 of the people who uh were treated this way or there was a 50 percent protection against dying from staphylococcal pneumonia now those figures were found in both england and australia uh they're a bit hard to to validate now because no one's going to to to use that sort of treatment but it was picked up in europe and became very common as an oral form of multiple bacteria and what we do know is that those bacteria they don't stimulate the specific immunity that we get the way we do it but they stimulate all the t cells so that everything's working in uh up regulated fashion and you get a level of protection against everything not a lot but some and so um so so the buculin is one uh there's bronchovac some i mean these there's a whole range of these products there's at least four or five of them uh different countries in europe so you just get an enough regulation of the whole the whole t lymphocyte system that's that's exactly it basically primes them so that fascination can work just that little bit better and there's a lot of data we do a lot of work on this uh but it wasn't nearly as effective as using the high-dose uh protected doses of particular isolates that we were using right right okay so you've got the general up you've got the general up regulating of the t-cell system and you've got you're more specific yeah um stimulus stimulus got it got it it's yeah it's a bit like walking into a classroom and you've got all the boys misbehaving and you kick them all in the pants and they all respond or you pick out one and say you're particularly bright you go to the blackboard it's it's the concept of specificity and non-specificity uh we're really going back to the dark ages of uh of the four humors in a sense no no but if it works i mean it is it's almost like it's almost like the the uh you're stimulating the innate or the specific isn't it again it's uh yeah well it is basically the idea it is it's innate immunity and the whole area of innate immunity has undergone massive change uh we we gave it a bad press uh initially by not really saying that has a level of specificity but what we do know now is that it's the innate system that actually gets the specific part the t cells and the b cells working in a directed and powerful way uh and maybe we can talk about that uh another time it gets we're starting to get into complexities of cells and molecules yeah but i think it is it's a valid point because we tend to think well there's an innate immunity in the specific community but in actual fact they interact it's always very complicated absolutely absolutely but i think by trying to do this in a layered historic way we can see how each part has its role has its part how can go wrong and how can uh be protective and useful yeah now i'm almost ready to go on to the cellular era robert but just before we do that um i've got serum sickness down okay as a note from this earlier period now i've never understood serum sickness oh in the last 40 years please enlighten me what the heck we've already talked about it uh we talked about hypersensitivity uh and i remember i said that there were three types differentiated by time one if you if you inject the antigen into your skin and it comes up within a minute it's immediate if you do it and it comes up in a couple of days yeah it's igg and it's intermediate if it's a couple of days ggg it's going to be a t cell which is later now that igg antibody and that delayed several hours delayed reaction that is serum sickness because what happens uh when and we went back one step further we talked about passive immunization you would for example take a pneumococcal that's the bacteria that causes serious pneumonia in young people you would kill it injected into a horse and make lots of pneumococcal uh antibody they'd take the horse serum and inject that into intravenously into a patient with pneumonia and most of them did moderately well but of course you're putting all this foreign protein into the serum and they're making an igg anybody against this and so about 20 or 30 percent of those people will fix complement and cause all sorts of complexes to be formed and these complexes with the antibody the igg antibody the antigen which is part of the the horse serum maybe igg anti uh protein uh and the comp the three of them form a complex that deposits in very small blood vessels in the kidneys in the joints in the skin in the gut probably in the brain and other parts as well but they're the main organ targets and once it fixes there it recruits an inflammatory damaging response with neutral white cells coming in called neutrophils as a result of breakup of the complement because it makes a factor which drags those cells in and so you get cells and edema and inflammation and so you get renal disease inflammation glomerulonephritis it's itis just means inflammation you get arthritis in the joints where you get those complexes deposited you get gut aches and pains uh you get uh skin you get uh urticaria or skin lesions uh wherever you get the complexes deposited you get symptoms and so this this is called vasculitis because it's inflammation of the very small blood vessels and it's caused by the antibody antigen complement complexes formed by the igg antibody in you and me getting the horse serum against proteins in the horse serum that's serum sickness that makes sense yeah these immune complexes the antibody in the anti-gender line basically all over and can cause as you say a wide variety of oh you can get very expensive conditions and of course of course maybe the reason i've never understood it oh yes yes you'd be it's because we don't do that that i've never seen it maybe that's why i've never but we see it in different forms there we see it with certain drugs and medications they can form complexes uh and create an antigen in the blood and you can get the same type of situation or you can get auto antigens involved and you get the same type of serum sickness that's what happens in systemic lupus erythematosus sleep you get antibody against soluble proteins from breakdown of nuclei of cells forming a complex the complement gets attached to it gets deposited and you talk to someone with lupus they'll say oh i get a rash in my face i get itchy i get aches and pains in the small joints of my hand the doctor tells me that i've got protein in my urine or a host of other problems depending on where the immune complexes deposit so that is immune complex disease you like serum sickness but it's part of autoimmunity because the antigen is not an external antigen like a drug or serum from horses it's an antigen from yourself so you're bringing together all these com simple comments that that makes sense now so so we with with the original same signal was sickness it was like a horse antigen our own antibodies forming those immune complexes which would get lodged in different tissues causing things like dementia and arthritis yes whereas now it's an auto antibody uh and a an auto antigen generating an auto antibody those two clump together forming an immune complex that lodges in different tissues and that causes localised inflammatory responses but it can be exactly exactly and the treatment pretty much is the same initially it was corticosteroids that were developed in the late 1940s and they're very powerful anti-inflammatory and all they do is dull down this host inflammatory response until the antigen gets cleared or it goes away with auto antigens of course doesn't always do that and you have to bring in more powerful ways of suppressing that immune response yeah yeah that that's really helpful because i can now see serum sickness which was a problem in the past viewed in context of current physiological processes thanks for that it was the details of sorting out serum sickness that led into understanding a lot of modern and all the work a huge amount of work was done on these problems in the 1930s and 40s and 50s uh compliment there are books that thick that thick written uh about compliments there's a check called kabat i know they had this terrible book by i think his name was quebec stuck when i was doing a phd stuck on my desk uh and i i just couldn't bring myself to read i've done that quite a few times when i've been studying for exams you have a particular book and you leave it on the desk and you hope that by looking at the cover because absolutely somehow yeah diffusional now i i think i think the next era we want to discuss robert is is the cellular era and and i think this started perhaps as early as 1940 but wasn't really recognized until about 1970 does that sound about about the right time frame for the cellular era yeah i i think right from the earliest days it was recognized that you couldn't explain all the immune protection or all the immune damage hypersensitivity just in terms of different classes of antibody and the idea of cells was around for a long time it got developed very much through the 20s 30s and 40s by people doing experimental work on animals for autoimmune disease and found for example a disease some of you would know about called hashimoto's disease which is occurs in two to four percent of women it's a thyroid autoimmune disease many people in my family have got so it's not at all uncommon and they could do they could create this disease in rabbits and transfer from a rabbit with the disease to another healthy rabbit by taking purified lymphocytes from the blood and so the idea of lymphocytes mediating an immune response was around but it wasn't until jacques miller uh working in london um french-born australian brought up uh shark uh found that if he took baby mice and took out the thymus gland which i talked about very briefly before if he took that out those mice would not develop a whole range of different types of immune responses and he was able to characterize the cells from the thymus gland which were given the very imaginative name of t cells because they came from the thymus gland just as b cells i guess come from bone marrow uh immunologists are not very imaginative really uh and and that of course i think they think b cells originally were discovered in birds goes back to the b they were i the bursts are fabricious uh that was that's yeah and it's just it's just handy that being that bone and burn again with the same i was a medical student at the time and it was such exciting to suddenly find that some of these poor unfortunate children with congenital immune deficiencies didn't have a thymus gland and suddenly uh through work done by robert good in new york uh we got we start understanding these immune deficiencies uh and then we had all sorts of changes and the big black box started shrinking uh jacques came back and worked at the hall institute in melbourne and he with graeme mitchell decided that some of these show that some of these t cells could help the b cell make antibody and so we had helper b cells and then another american showed that some t cells could turn off the b cell making antibody and so all of a sudden the huge change that came was that we went from an antibody era to a cellular era now to be fair to mcfarland burnett mcfarland burnett was the person who introduced the idea of the cellular era by simply showing that antibodies well he what he said was that b cells have antibodies on their surface as a receptor and this idea of cells with specific receptors came from out of the antibody story when burnett developed his great idea of selection as a way of identifying why we had antibodies against outside antigens but not against yourself and what burnett said was that those self-reacting b cells would be destroyed before birth which in a sense they are at the ones that weren't would be there to react against all those huge numbers of antigens uh outside uh the the body and this led to the whole concept and idea of regulation when you had t cells that could control the up and down regulate the b cell uh and in fact burnett came up he had to come up with an idea for autoimmunity and that's when he said ah we have somatic mutations going on in these cells and finally they make an antibody against yourself and he called these the forbidden clones and that was my introduction to autoimmunity i was a first-year medical student and someone came back from a talk that uh sir mack gave down in melbourne i i grew up in sydney uh and that and they said there's this man called burnett and he's talking about the forbidden clone and so i i just thought this is what i want to do i want to be a forbidden clone doctor which is what happened uh but it all began with burnett and then jacques miller came back and worked with burnett and gus nossel at the hall institute and came up with the idea of regulation through the t cell and of course that's just gone on now to the complexities of uh amazing complexities of of of cytokines and we could talk about it perhaps next time so so so these forbidden clones are basically b cells that would contain auto antibodies that are filtered out by the thymus glands before exactly that's how burnett saw it because remember this was about four or five years before uh jacques miller had actually discovered the t-cells uh were from the thymus clan so everything was very antibody orientated and what bernie did is by saying i think that there's a selection process going on at a cell level and the way it's done is the receptor is actually the antibody sitting on that cell so you've got every b cell has specificity yeah and this antigen will only react with that and then it'll divide and you've got lots and lots of them and you get lots of antibodies uh in response and that was the beginning of the cellular era which was consolidated when shark miller came up with the t cells so we had b cells and t cells took a long while to come up with the t cell receptor and so yeah sorry the the b cells with this specific uh clone for a particular specific antibody exactly when that's selected but when that's selected by the antigen these these b cells with a specific antibody will divide and become plasma cells exactly exactly and you'd have lots of them and it's the it's the plasma cells that then and millions of them billions of them and these plasma cells are these the ones that actually secrete the antibodies into the plasma to give humeral that's right you've got one each plasma cell produces this plasma cell produces one antibody one type of antibody and they divide and uh yeah but they're excreted into the humans of the body that they're the factories they're not they're not they're not bound to the membrane no no no no they're this affect their factories they're making the antibodies and secreting it and if it goes wrong you get a disease called myeloma i've never i've never quite i've never yeah i've never do that i've never quite got that before so in the b cell the antibody is attached to the the the surface membrane of the b cell but when they differentiate into plasma cells the plasma cells actually secrete the antibodies into the into the humerus the b cell actually makes the first antibody that's plastered on the cell membrane it makes it but when it transmits into a factory it's called a plasma cell and instead and it's just its only purpose in life is to make that particular antibody uh and uh um if it if it goes wrong and it becomes a cancerous plasma cell you have a disease called multiple myeloma and you get all sorts of problems by having huge amounts of igg or iga or ige or all the different classes of antibody type myeloma cells nasty disease so myeloma is basically a cancer of b cells robert is that the best way to look at it it's a cancer of plasma cells um most of the cancers of b cells are more called lymphomas so lymphomas they can be t cells but most of them are b-cell lymphomas and there's a huge variety depending on what stage of the b-cell development becomes malignant right okay it's quite a subtle distinction but i see that so so basically we know these small lymphocytes we we have that now we have the t helpers the t suppressors and the two cytotoxics that's right we didn't talk about the clean cycle and the helpers are stimulated no but but but the t helpers are stimulating the b cells to make that's right the antioxidants and of course it's the t helper cells that are damaged by the human immunodeficiency virus isn't it exactly the cd4 they were all given little names and this is the cd4 so they have a receptor which the cd4s yeah with which the hiv the the aids virus can bind to and destroys and you can measure how sick the person is or likely to become by just measuring the number of t cells in in the blood and then when that when there's been enough immune response as it were the t suppressor cells will inhibit the the proliferation of the b cells and the plasma cells yes this was a fairly primitive concept back in the 70s and 80s uh it was thought that the the b cells and also the the t cells that were doing things were regulated by different subsets of helper or suppressive t cells the idea of regulation was a very good one and lots of loops of ancillary regulatory mechanisms became involved it was never never simple but the concept is one of regulation and then um i'm not sure john if you want to keep going now or do you want to because we we now move on to the era of no i think what i think i think i think i think we'll probably leave that hanging in the air now we're sort of into the excitement of the area of cellular immunity aren't we yeah yeah i just thought what one one more question thing i don't quite understand is that these t helper and suppressor cells will they help and suppress the t cytotoxic cells as well as the bees yes they will yes they will and uh when we progress and talk about how this occurs um and the whole there's a raft of nobel prizes get given at every junction uh as we better understand the uh the immune system uh we'll talk about the antigen processing cells or dendritic cells uh which are really from the innate system coming together with the adaptive or specific immune system and that's that's a story in itself but very important because uh it relates to uh regulation autoimmunity um host parasite relationship so we can actually finish by coming way back to that host parasite relationship we've suddenly gone from the very beginning of a a crude um that's a crew but a very simple system where you've got the b cell or the antibody if you like interacting with part of a virus or a bacteria and the regulation was simply getting rid of the bacteria getting rid of the virus so there's no more stimulus we've moved on uh through systems where the innate a mechanism innate immunity was critical to getting an outcome for protection or if it goes wrong and it's inappropriate and excessive the foot soldiers go off like a hamburger grenade and cause tissue destruction and then we've moved on to the fact that there's another arm to the immune response called cells first thought of in the old hypersensitivity testing couldn't explain at all with antibody here are the cells and then burnett saying well let's give some authority let's give some ownership to cellular immunity by putting receptors on their surface let's make anybody know about antibodies and these are b cells another kind shark miller to say well i found out what the other cells are i'm calling them t cells or thymus derived cells and so we have this collaborative system and regulation started taking off in earnest and the black box started shrinking incredible that's a hundred years of immunity robert i'm i'm quite uh yeah i'm quite exhausted that's to tell you the truth it's so interesting but so much yeah that's that's true that's true for the next enthralling episode you're going to have to come back to learn about monocytes macrophages dendritic cells the way that these are but we'll make it very simple and we'll also be moving on uh always we always make it simple we simplify without being simplistic then then we have to move on to the the immunogenetic era and the implications of that for things like allergy immune deficiency immunosuppression and of course we'll get around to uh cancer as as well so the molecular era and the immunogenetic era to come and then we'll finish with the cutting edge but for now robert uh we've covered 100 years of immunity i've certainly learned so much and i really think it's important to well firstly we all stand on the shoulders of giants we do and we've talked about a lot of giants yeah i mean yeah and it's right to pay homage to these people but as well with this complicated field it is it is it is the best way to understand it because it looks i guess we try to make it understandable because it it the principles are understandable and simple but there's there is a giant at every flexure point and at every fletcher point there's at least one no real prize the the conceptual ideas uh have just been so mind-blowing and yeah it's very hard not to get excited about immunology i'm a little biased no no i agree and and and we're just sort of almost niggling at the surface of the comp the complexity of of of living organisms and human physiology which is i thought what yeah never what i find very interesting john is that that i've been lucky enough to live and work through 50 years of change and when i first as a student first got involved and interested in immunology it was a huge black box you know we were just coming out of the antibody europe um shark miller i think it was 63 i was doing a year of science research in molecular genetics and this idea came you know someone's taking thymuses out of baby mice when i got over the fact i thought it was rather cruel that these mice couldn't make uh i couldn't make t couldn't make cellular immunity and the next year i was doing a pediatric term and robert goode the other great thymus inventor if you like had been was visiting sydney and we had a patient with what's called de george syndrome which is congenital absence of the thymus so within one year of of of uh shark describing uh this this amazing uh change in biology um here i was seeing a patient that that didn't have a thymus gland now these days of course we we can save a lot of these children by um by genetic transfer and and transfer of cells and whole range of very clever technologies but of course in those days it was was just not possible always good though to link the the theory to the practice and then well that's what i like yeah the the this is also how how the whole learning process has developed sometimes robert thank you um it's your bad i'm just going to say i i think my greatest what's going to say you're a bad time no no i don't go to bed but what i what i find so disappointing is that more or less at the end of my my clinical and research career all the things i wanted to have when i started are suddenly starting to appear you know we can make huge inroads now into cancer we understand autoimmunity uh we're doing really uh you know a very good friend of ours has just had t-cells sent off to america to re uh to re-prime a woman with lymphoma and the lymphomas disappear uh now this was unimaginable 10 years ago just amazing yeah and uh yeah what will the next 50 years hold of course another well you wonder don't you i mean look what's happening fascinating question we have telephones no yeah robert um thank you very much um thank you for your um lifetime the dedication to this as well this has just flowed from that this has been a very easy interview to conduct actually because it just um you've lived through it and there's no substitute for that so so great pleasure bye come back for the next episode

Channel: Dr. John Campbell

Views: 346,867

Keywords: physiology, nursing, NCLEX, health, disease, biology, medicine, nurse education, medical education, pathophysiology, campbell, human biology, human body

Id: KGzqh7PeAvg

Length: 71min 12sec (4272 seconds)

Published: Mon Aug 15 2022