0:02 now today our discussion is about type three hyper sensitivity reaction type three hyper sensitivity V reactions now to understand the type three hyper sensitivity reaction first of all you must know the basic fundamental that this is a disease it's immune mediated tissue damaging condition it is immune mediated tissue damaging condition due to deposition of immune complexes formation and deposition of immune
0:49 complexes which lead to inflammatory reactions what are the things listen what is there the immune complex formation immune complex Lex formation right and these immune complexes lead to inflammatory leens they lead to inflammation is that right and in this condition the antigen is not fixed to any particular tissue antigen is free uh or wherever antigen antibody reaction occur antigen is not part of that tissue antigen is free antibod is also free free antigen
1:34 antibody make the complexes which may get deposited in different parts of the body or sometimes antigen may go and deposit in some tissue first and antibody may follow for example in post strepto coal glar netis strepto coal antigens get deposited in the GL basement membrane and then antibody may follow or in the the same condition some of the stto cocal antigen and anti-to cocal antibodies make immune complexes in circulatory system and then those immune complexes get deposited in gleri and there at GLA basement membrane inflammatory reaction is activated so the basic concept is that antigen in this case maybe antigen in this case may
2:22 be endogenous or exogenous but it is usually free for example endogenous antigen may be antigens in these cases may be exogenous or endogenous exogenous antigens may be bacterial antigens or maybe fungal antigens right and maybe viral antigens right for example strepto cocal antigen in case of postal glal nefritis then fungal antigens in case of farmer's lung which is localized type 3 hypers sensitivity reaction viral antigens like Hepatitis B antigens are involved in
3:07 poly arthritis NOOA or antigens may be endogenous for example in SL right you find DNA right DNA or nucleo protein may act as antigens against which antibody reaction is there so antigens may be endogenous or maybe exogenous and these are free antigen they are not intrinsic to the tissue to which reaction is occurring these antigens and antibodies are antigens react with the antibodies and antibodies may be IG G or they may be IG M and then this antigen plus antibody which is making a immune complex this is immune complex
3:52 right this will through complement activation plus through inflammatory cells like neutrophils it will lead to severe inflammatory reaction inflammatory reaction now sensitivity reactions type three hyper sensitivity reactions are classified as generalized reactions generalized reactions and they may be localized reaction localized reaction generalized reactions are also called serum sickness type reaction the
4:40 serum sickness serum sickness like reactions right and localized reactions are also called arus reaction now first I will go into detail of generalized or systemic reactions type three hypers sensitivity reaction or immune mediated tissue inflammatory reactions immune complex mediated immune complex mediated inflammatory reactions in multiple system or generalized in the body first I will discuss into detail and then I will talk about localized
5:27 reaction when we talk about generalized this reaction we say it is serum sickness like reactions right so first of all we'll talk about what is the concept of serum sickness right because serum sickness type reactions were occurring in past very frequently not now that frequently in past we were using horse serum for Passive immunization right and when we were introducing horse serum for Passive immunization of human being let's pose against d theia right so after injection of the h serum after a few days patient will develop multi- systemic inflammatory condition which was called serum sickness these days serum sickness type reactions or type three hyper sensitivity reactions are not most
6:13 commonly due to foreign serum serum these days in modern era such reactions are most commonly due to drugs so it's worth writing that in the modern era we are using foreign serum less frequently so serum sickness type reactions are no more mostly due to foreign serum uh these days serum sickness like reactions or type three hypers sensitivity generalized generalized reactions are due to drugs right but we'll take a prototype serum sickness disease and we'll talk about that right let's talk about in detail the one example of serum sickness disease how it can be induced and what are the uh pathological changes
7:00 in body how immune complexes are formed how do they circulate how they are deposited how they produce the inflammation what type of clinical presentation is formed in serum sickness and then we'll talk about Sim similar other conditions right so let's talk about serum sickness now let's suppose here is your circulatory system here is your circulatory system right and
8:04 here we make your immune headquarters this is your immune system immune headquarters right here we make bone marrow house bone marrow house right now we'll take an example that what really happens already you know that in the bone marrow what really
8:49 happens that there are stem cells right and stem cell go into two lines and from these line there is AR line and there is okay there's myid line and there is lymi line there is lymi linage lympho linage and my linage now out of this myed right one of the this mid linage is responsible to produce rbcs and and it is responsible to produce myet linage responsible to produce
9:36 platelets and this line is responsible to produce lucos sites lucos sites other than yes Luc coytes other than lymphocytes lymphocytes because lympocytes are coming from lymi line now we have a story that this is a particular patient what first we are trying to understand the normal thing that this person has stem cells stem cells divide into lymi stem cells and mid linage cells lymi stem cells will make lymphocytes and mid linage will
10:22 produce rbcs and platelets and Lucy other than the lymphocytes am I clear to everyone now let's suppose that here is your stem cell of the myet side this is the stem cell of myid linage and this was the stem cell of lympho linage is that right let's suppose this person unfortunately this person unfortunately developed autoreactive t- cells he developed autoreactive t- cells lymphocytes and
11:08 unfortunately these lymphocytes reacted against what is this myid cell in this particular patient where we are taking example of serum sickness we are first making the foundation of a understanding that this person has developed a defect in immune headquarters and immune system is making immune system is making yes immune system is making t- cells and these t- cells are autoreactive te- cells and unfortunately
11:53 what these T cells have done these t- cells have reacted with the Mite cells the this was the myet cell myet stem cell and these are Auto reactive t- cell right and this Auto reactive T Cell attacks the myet cells and destroys the Mite cells now if you your these melet cells are destroyed uh number of rbcs will go up or down number of rbcs will go down number of platelets will be also going down and number of lucose ites other than the lymphocytes will be also going down so this person will develop three problems number one he will develop anemia number two he will
12:38 develop thrombocytopenia and number three he will develop leucopenia is that right but lymphocytes number may be normal am I clear now so you can say this person is having a disease in which his immune system is attacking inappropriately his mid stem cells and destroying the destroying the arthid linage and destroying the thr thrombo atic linage and destroying the granite monoy linage right so this patient develop severe anemia right this patient develop problems of
13:24 anemia right with that this patient develop thrombo thrombo cyto penia with that this person develop Luco yes please Pia when someone has less rbcs less platelets and less white cells we say this person has developed what type of problem if all these three problems are there yes as a group what is this problem called yes please you are all doctors what is this condition called right when there is thrombocytopenia anemia and leucopenia when these three things are there we
14:10 call this condition yes please pan cytopenia pan cyto penia have you heard of it pancytopenia now bone marrow will be hypocellular normal cellular or hyper Cellular in this condition of course this person will be having all the features of anemia pellar and fatigability with bleeding Tendencies and with increased frequency and sity of infections is that right so this patient in the peripheral circulation will show pancytopenia is that right this person will show pancytopenia uh but blood is
14:55 showing deficiency of rbcs wbcs and plat but when you do bone marrow picture what you find in the bone marrow picture yes please what you find in the bone marrow bone marrow will be hyper cellular normal cellular or hypo cellular of course bone marrow cells are being destroyed bone marrow cells are being destroyed as bone marrow cells are being destroyed so bone marrow is hypocellular so due to this amune IM attack autoimmune attack on the mid stem cell patient develop hypocellular bone marrow or hypoplastic bone marrow hypo cellular bone marrow or other term which
15:41 is used is hypo plastic bone marrow and with the hypoplastic bone marrow patient develop pancytopenia so hypoplastic bone marrow with pancytopenia is which disease you know it hypoplastic bone marrow hypoplastic bone marrow with pancytopenia what is the name of the disease you know it when I will tell you you will say you know it I'm very sure you know it you don't want to share your knowledge with me yes you know that this I can bet you know it have you ever heard of yes R have you ever heard of a plastic anemia this is a plastic anemia a plastic
16:26 anemia is a misnomer you know it is not only anemia it is thrombocytopenia plus leucopenia it is a misnomer it should be ideally called aplastic pancytopenia but I don't know why its name is aplastic anemia but why we call it aplastic anemia because bone marrow is a plastic and peripheral circulation is showing anemia but actually not only anemia peripheral circulation shows thrombocytopenia as well as leucopenia does that right so this is a patient of aplastic anemia what is this this whole story is a patient of aplastic anemia and patient with aplasto anemia has hypoplastic bone marrow or aplastic bone marrow
17:13 with pancytopenia and the peripheral blood picture am I clear of course it's lifethreatening situation is that right if rbc's become very less patient become very weak oxygen capability Capac transferring capacity is used platelets are very less patient has a high tendency to bleed and of course what really kills very frequently is very low neutrophil and other white blood cells and patient cannot defend against infections and patient develops bleeding Tendencies and repeated infections and very high risk of death now how do we manage this patient there's so many ways to manage one of the way to manage is we give animal derived antibodies to the
18:00 patient let me tell you how look here let's suppose here is your friend let's suppose this is a horse my drawing is not that good about the horse it's an innocent horse is that right now if we take look if you take the cell what is this cell autoreactive cell T Cell so if you take t cell antigens what we take t- cell antigen and inject to this inocent horse what we have done we have taken human te- cells and removed the human t- cell antigens and human t- cell antigens have
18:46 been injected to the animal do you think for this animal human t- cell antigens the self for foreign foreign so R knows it so immune system of this animal when it will receive these antigens it will make the antibodies what it will do it will make the what antibodies now these antibodies when we bring from animal out these antibodies are derived from animal from the horse and these antibodies are against the human tea cells and we injected the animal with the t- cell antigens and animal provided us with the antibodies against the t- cells these antibodies
19:32 these antibodies are called yes what they are called a t GS atgs mean what antiyoy globins anti-t cell globins these antibodies are anti T cell globins this is that right now we give injection of this atgs we give injection of this atgs to this patient to our patient we introduce atgs right what are atgs these are special antibodies which are horse derived antibodies is it right and these
20:18 antibodies are directed against human T cell I hope up to now the story is clear now this antibodies are given as treatment modality these antibodies are given as treatment modality and we expect that these antibodies should attack these t- cells they should attack these t- cells and if these antibodies attack these t- cells and Destroy these t- cells it means that destruction of my cell has been reduced is that right attack on the again from the animal you derived atgs in some books it will be written ALG but don't
21:04 mind it ALG also stand for anti-lymphocytic globin but because they are not against the B lymy they're specifically against the T lymy so more appropriate word is atgs so when animal is providing us with the atgs we inject the atgs to this patient right these antiyoy globulins or atgs attack the D cells of the patient of the aplastic anemia and when when in aplastic anemia T cell are destroyed naturally immune attack on the bone marrow is reduced right because when immune attack on the bone marrow is reduced what will be the result when immune attack on the bone marrow is reduced that these cells will again
21:51 start proliferating the cells which are not which was still alive right they will start proliferating and patients RBC count will start going up platelet count will start going up and and Lucy start going up is that right we say bone marrow will also start recovering and peripheral blood picture will also start recovering now you must be thinking where is our serum sickness we did not talk about that thing yet okay that is going to start very soon listen up to now patient did did not have any problem you injected the horse antibodies to the person these antibodies were atgs and these atgs reacted with the human tea
22:38 cells destroyed some of the human te- cells so attack autoimmune attack on the bone marrow was reduced so bone marrow cells started proliferating bone marrow picture start improving and you can say bone marrow start becoming more cellular and of course end product of bone marrow activity will increase in the blood so patient has increasing rbcs wbcs and platelet count so we say peripheral blood picture also start improving up to now everything is okay but what happens after few days of injection of this horse serum or after a few days of injection of atgs some of these patient who are injected with atgs they develop a special type of illness they develop a special type of
23:24 illness they develop again fever they develop generalized lymphadenopathy they develop protein UA and hematuria they develop rashes they develop polyarthritis they develop pericardial pain or pleuritic pain is that right and multiple vascul lons right and this whole complex is called serum sickness or type three hypers sensitivity reaction now question is this that how atgs atg triggered the serum sickness like disease what atg did in the patient body that he developed such a special type of illness let me answer it actually these
24:10 atgs or horse antibodies are taken up by what is this immune headquarter and our immune system human immune system will consider these antibodies as self or foreign our immune system will take these antibodies as foreign so what happened even though these antibodies are good for us that they are destroying our tea cells and protecting us from the autoimmune disease but unfortunately these are taken up by the immune headquarters and in the immune headquarters atgs appear as antigen atg which are coming from the horse even though these are antibodies against our T cells but these horse derived antibodies are recognized by our immune
24:57 system as foreign proteins so these atgs will be taken up by the antigen presenting cell antigen presenting cells and antigen presenting cell will take up these foreign proteins and present them to the T helper cells and you know that t helper cell will act on the B cells and convert them into yes plasma cell and these plasma cells will start Mak making another class of antibodies IES and these black antibodies are the antibodies which are against the atgs these black antibodies are produced by the immune system when horse antibodies trigger the immune
25:43 system is that right an immune system take the horse derived antibodies or immune system take the atgs as foreign proteins and immune system will make antibodies human antibodies directed against the horse antibodies how the horse antibodies will be processed taken up by processed and presented by the antigen presenting cells to the T helper cells and t- helper cells will activate the B cells into plasma cells and these plasma cells will make anti atg antibodies So eventually this patient will develop what thing there he will develop yes anti atgs
26:29 that is am I clear up to now no look atg are now behaving as antigens and anti atgs are behaving as antibodies is that right now if still in circulation now what will happen atgs and anti atgs will react with each other right and then uh let's suppose this is the what is this atg and what is this reacting to atg anti atg is that right now this is becoming an immune complex so there will be lot of immune complex formation within the
27:15 circulatory system all these immune complexes will be formed within circulatory system as atgs will react you can say atgs will react with the horse antibodies now these immune complexes are there now just formation of immune complexes is not enough to produce the disase because in a normal person if larger immune complexes are formed immune complexes with larger size are
28:00 formed these are very efficiently removed from circulation by mononuclear fosic System what are these mono nuclear fosic system of course monoy derived different macres or CER cells or right all those cells now this is the duty of what is the duty of this this is the duty
28:47 of this is the duty of these macro phases that these monuclear fosic system should eat up all these what is this ammun complexes this is a normal phenomenon normally in human body antigen antibody complexes do form and these antigen antibody complexes are normally very efficiently removed by mononuclear fosic system so they do not circulate unduly and they don't deposit here and there unduly rather it is one of the normal pathway of elimination of antigens out of our body that antibodies should react with the antigen make the complexes and these complexes should be eliminated by fosic process
29:36 of monuclear ftic system now sometimes what happen if in this particular patient either immune complexes are very small because this monuclear fos ftic system is very very efficient in phagocytosis of larger complexes but if patient is making small immunal uh you can a small immune complexes then they cannot be efficiently removed or efficient remover may be impaired because there are so many immune complexes that this clearance mechanism is overwhelmed right or someone has intrinsic defect in his monuclear fosic system so any one of these condition either complexes are very small very
30:23 small complexes tend to circulate more and they less evidently bind with the clearance cells or these cells are overwhelmed by the immune complexes or they are having some intrinsic defect any one of these things will lead to impaired clearance of immune complexes from circulation and immune complexes will circulate in our systemic circulation for shorter time or longer time they will circulate now longer time and if they're circulating for longer time then they will start depositing in multiple areas depending upon they will start depositing in multiple areas in the body if they are not efficiently removed
31:08 now in which tissues they will deposit it depend on hemodynamic characteristics of that tissue it depends on that uh what are the charges or lce size or valency or Affinity of these complexes but anyway let's suppose that this immune complex this was the you can say this was the antigen and this was the anti atg now this is the immune complex this is the atg and this is an atg this is derived from horse and this is derived from Human immune system and now they're making complexes within the circulation and they have not been efficiently
31:53 removed what will happen to them now the M deposit right in some part of the vascular system right they may deposit into some part of the vascular system let me show you that to which part they are depositing I'll will show you there are some certain areas where circulating immune complexes love to deposit now this is immune complex right which which could not be removed now this immune complex which could not be removed let's suppose it binds here with the
32:38 endothelium and when this immune complex you know this has an active FC portion if some neutr some neutr or macras or mast cell is irritated by this immune complex these cells May produce vasoactive they may produce vasogenic Vaso genic substances substances again let me tell you what really happens in this patient immune complexes were formed right formation of immune complex occur around 10th day right 7 to 10 day after the injection of
33:24 atg because 7 to 10 days are required by the immune system to capture process and present the atgs to the tper cell and tper cell take time to activate the B cell to convert into plasma cell so 7 to 10 days patient develop anti-s and then immune complexes are formed if immune complexes are not cleared efficiently then what really happens that these immune complexes start depositing in multiple part of circulation for example here this immune complex deposit then active FC portion of human antibody May activate some inflammatory cells and those cells May produce vasogenic substances like histamine or other prostaglandins or like tumor necrotic factors and these vasogenic substances will produce some
34:12 vasodilation plus they will produce endothelial shrinkage and Inter endothelial gaps will be formed what will happen interendothelial gaps will be formed if interendothelial gaps are formed it means that there is increase permeability of microcirculation wherever these complexes are depositing right wherever these complexes are depositing that what then what will happen that these complexes May extra visit and they come into yes these complexes may come into deeper layers of vascular area so these complexes may become you can say slightly embedded into wall of they move from endothelial site into the wall or
34:59 media of the vessels am I clear now we have seen how the complexes are formed and deposited again listen phase one was complex formation how immune complexes were formed antigen triggered the immune system immune system made the antibodies right antigen antibody complexes formed in circulation and they could not be cleared this was phase one phase two was these complexes start depositing into multiple Parts in the body I will discuss later which are the parts once they deposited the next phase is the third phase is trigger of inflammation initiation of inflammatory reaction
