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Ziad Elnasser Aisha

Tuesday,

Complement (cont.) &

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By the name of Allah

Immunology Lecture # 17

Tuesday, 26/7/2011

Done By: Aisha Gharaibeh

Asslamu Alaikom Please consider the following abbreviations throughout this lecture:

Ab = Antibody APR = Acute Phase Response

CR = Complement Receptor CRP = C-reactive protein

EBV = Epstein-Barr Virus ESR = Erythrocyte Sedimentation rate

Ig = Immunoglobulin IL = Interleukin

IFN = Interferon NK cells = Natural Killer cells

MAC = Membrane Attack Complex MBL = Mannan Binding Lectin

RBC = Red Blood Cell TNF = Tumor Necrosis Factor

Announcements by Dr. Elnasser:

- Well have the 2 nd midterm exam on 13 th of August.

- Next week will be Ramadan, so HAPPY RAMADAN . I hope you looked at thenew schedule & see the new timetable, so our class will start at 10:00 AM ratherthan at 10:30, Im sure you know that!

COMPLEMENT (cont.)Well continue with the innate immune system. Yesterday, we were talking about the

complement where we have 3 major pathways ( 1 the classical pathway, 2 the alternative(properdin) pathway, & 3 the MBL pathway). The ultimate goal of complementactivation is destruction of cells where the complement is fixed on its surface. 2 nd

component of the complement -like C3a, C5a- act as anaphylatoxins, so they stimulatemast cells & basophils so release their vasoactive amines so we'll see inflammationassociated with that. Those two [C3a & C5a]act as chemotactic factors, they call uponphagocytic cells to come into the area which help in the phagocytosis process as well,& we see other mechanisms or functions of the complement: it helps in thephagocytosis process in what we call opsonisation (the property related to Igs theIgG type- & the receptor of the IgG, so IgGs are opsonins), the same thing in thecomplement, C3b can act as a complement as well.. so you have both (Ab & thecomplement) & then phagocytosis is going to be very efficient.

And also we'll see that the complement system is going to help in the clearance of

immune complexes that we have in our body, so the clearance of immune complexes(whether those are coarse / large complexes or fine immune complexes). i.e., we'll see

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that if we have any of the complement components that is deficient, we'll see thatthese immune complexes will stay in our body & will inflict injury, like systemic lupuserythromatosus (SLE) & others.

And we went through each of these pathways:

- The classical pathway: we call it the classical because we start with the C1 as 3

components: C1q, C1r, C1s. C1q has 6 heads & it's the first to bind, gets activated &activates C1r. C1r has 2 heads & activates C1s. C1s is going to activate C4 & C2. Those2 [C4 & C2]are going to be splitted into smaller components & larger components.

The smaller components have other functions, for example, C2a activates the kininpathway, & C4a acts as chemotactic factor (or anaphylatoxin, but into a smaller scale).The larger components (& here we call it C2a & C4b, in other books C2b) will act as theC3 convertase, so the C3 convertase acts on C3, splitting that into C3a & C3b. so C3aacts as anaphylatoxin & chemotactic factor. C3b binds to the surface of the cell toform what we call C5 convertase, so we have 4b2a3b, form this C5 convertase to splitC5 to C5a & C5b. C5b binds to the surface & starts the process of what we call themembrane attack complex. So the membrane attack complex starts with C5b whichbinds & activates C6 binds & actives C7, so C5b67 activates C8. C5b678 starts theprocess initially of making holes in the cytoplasmic membrane but the real hole occurswhen C9 gets activated & joins so a major leak is going to take place in the cytoplasmicmembrane & the cell is going to be destroyed.

So started with C1, ended with C9, & all of these cascade reactions have to follow,& we said that we have some regulatory mechanisms at each step, the major one is the

production of what we call C1 inhibitor. When the reaction needs to stop, C1 inhibitorbinds to the C1q preventing its activation & so no C1r will be activated & the processwill stop.

We said that if C1 inhibitor is missing then the patient is going to have a disease wecall it angioneurotic edema where any minor infection or trauma (sometimespsychological cause or unknown cause) then the reaction keeps going on & on, & all thecomponents are going to activate the mast cells & basophils & well have lots ofinflammatory mediators, & edema is going to develop, & lots of tissue, & kinin cascadewill be activated & all of these will lead to the disease angioneurotic edema.

We said that we have other mechanisms of regulation that act on C4b binding todecay activating factor, co-factor of the cytoplasmic membrane, CR1 also, so all ofthem act in the inhibition of C3 convertase at this level.

And we have at the level of the MAC, the CD59 is going to bind to C5b67 preventingthe activation of C8 so itll stop & the reaction here will not take place. And we saidthat if we have any deficiency of the complement components then were going tobecome immune compromised. And they have noticed that if they have deficiency ofany of the components of the MAC. For example, people become more susceptible forpyogenic types of infections, like Niesseria species (N. miningitidis in particular), & in

your book it says about a patient who has this deficiency in the family, how they start

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to develop N. meningitides types of infection. So the complement plays a major role indefense of those types of infections & how if any of those complement deficiencies ata higher level also then immune complexes cannot be cleared up & you developautoimmune diseases, like systemic lupus erythromatosus & so on.

So its so important to know about complement & its activation, & we said that C3has the highest concentration in serum & it makes sense because in the pivot where allthe 3 pathways end up.

The alternative pathway starts at C3. We said what activates the classical pathwayis 2 IgGs or 1 IgM, while in the alternative pathway its lippolysaccharide of bacteriaactivates C3 which is splitted into C3a & C3b. C3b binds to the surface & it dependswhether the surface is self or nonself: if its nonself then factor B will bind, theminute factor B is bound itll be hit by factor D splitting the factor P into smallercomponents: Ba & leaves behind the bigger component Bb. So we have C3bBb, this iswhat we call the C3 convertase, it has a short half life, so when its bound to P (we call

it Properdin ), itll have a longer half life, itll act on C3 [factor P stabilizes C3 convertase thenC3 convertase will remain activated & cleave more C3] & we call that the amplification loop ,more C3b will develop, itll bind & develop, & when we have 2 of the C3b this is going toform what we call the C5 convertase that will act on C5 splitting C5 into C5a & C5b.C5b the same- starts the MAC, & C3a acts as anaphylatoxin & chemotactic factor, &we said if the surface is self immediately when C3b is bound & a factor we call it H isgoing to bind so now we have C3bH which is going to be hit by factor I (inactivatingfactor) destroying C3b into inactive C3b. And those have receptors on cells as well atthe same time & the reaction will stop. This is how the alternative pathway isregulated.

Then we talked about the MBL where the mannan-binding starts here by theactivation of C4 & then C2 & the processes go to C3 like those in the classicalpathway. The only difference is that we dont have C1 & mannan-binding here activatesthis pathway, so the outcome is almost the same.

This is a summary of what I was talking about: {referring to slide 11}

- Lectin pathway: lectin, from the collectin, like the surfactants -that we have in thealveoli- binds to carbohydrates of the bacteria & activates C4, C2, & then C3.

- Classical pathway: immune complexes, Ag-Ab reaction, starts with C1, you need IgM& 2 IgGs, start with C4 then C2 then C3

- Alternative pathway: starts directly on C3, we dont have C1 or C2 or C4 (this is reallyimportant!), secrete unstable on surfaces, self inhibitors by the H & the I.

** Any deficiency in complement components leads to defected immune response! (&I want you to remember that)

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So this slide here shows thecomplement. The complementcomponents are inactive unlesstheyre cleaved. When theystart to become cleaved theybecome active. And then the lastfragment has enzymatic activitybinds to the surface, the smallercomponents -like C3a, C4b, C5a-go & act as anaphylatoxins &chemotactic factors, so theybind to the surface unlesstheyre blocked by an inhibitoras we said.

The amplification steps : we talked about that in the alternative pathway..

Once one component is activated it will activate downstream components, this iswhat we call a cascade.

C2, C4, C3, C5, and C6 cleaved into small and large molecules (enzymes) activates the next component.

Inhibitors could bind into these in the way & stop the reaction.

Small fragments of C3 & C5 (i.e., C3a & C5a) act as anaphylatoxins responsiblefor the inflammation that we see when the complement is activated.

This is here how the complementmediates the inflammation, & you seehow these white blood cells will come

out from the blood vessels into thearea by chemotactic factors.Anaphylatoxins increase the vesselspermeability, leukocyte adhesion isincreased & then they will pass intothe area. When leukocytes reachtissue, anaphylatoxins stimulatephagocytosis & degranulation will takeplace.

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And we said also that complementcan clear out immune complexes as

you can see. They can first activatephagocytes, they act as opsonins. So

you can see here, we have areceptor on the surface of amacrophage, the receptor binds thecomplement, & a complement isbound here to immune complex soitll be taken inside, it helps in thephagocytosis.

Also complement can activate Bcells (& we talked about that before), if

you remember the complementreceptor 2, the CD21 (which is thetarget of the EBV) can act asreceptor for the activation process& also clearance of immunecomplexes whether those areinsoluble or soluble, insoluble immunecomplexes may form in the tissue, complement binds Ig F C portions, so you can see howcomplement can help to solubilize large complexes into small ones.

Also if you look to the surface of the RBC here, it has a receptor for thecomplement, so when you have an immune complex that binds to the surface of theRBC, RBC can carry those immune complexes in the circulation & clear those immunecomplexes in the spleen. A complement binds to receptor on RBCs which transportimmune complexes to phagocytes in the liver & spleen, they bring them to the liver &spleen & clear those immune complexes up, or if we dont have these complementcomponents, the immune complexes stay in our body, they will precipitate in the tissue& inflict injury into those tissues.

So as a summary of the complement effectors :Anaphylatoxins: inflammation of mast cells & basophils. C3a & C5a. We couldhave C4a as well in smaller proportion.

CRs

In order for those to work, we must have receptors for those complementcomponents on cells. The MBL, C1, C4, C3. And when we talk about CRs, we talkabout 4 receptors: CR 1, 2, 3, &4.

- CR1 is mainly for the C3b & MBL as well

- CR2 mainly for the activation of CD21 & the activation of B cells.

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- CR 3 & 4: fragments of C3b so 3&4 help in the phagocytosis process as well.

Opsonization : can be done by an IgG (we call it opsonin), so you must havea receptor for IgG on the surface of the phagocytic cell, so IgG blocks by itsplace, so the binding site will be cleared so the organism will bind to theattachment sites of the Ig & itll be taken in. The same thing with thecomplement, has C3b receptors, so the C3b on the surface of the bacteria willbind to its receptor & we have both (the IgM & the complement), then thephagocytosis comes very effective.

B cell stimulation : occur through CR2, CD21, C3 as recepotr for EBV too.So the B cell gets infected by binding to EBV by binding to CR2.

Immune complex clearance : Large insoluble complexes become Solublebecause of the complement (C4 and C3) bind to surfaces of RBCs & fixmacrophages. If complement is deficient, clearance of those immune complexesis going to be affected, & we could end up with systemic lupus erythromatosus(this disease is simply DNA-antiDNA.. so our body reacts against its own DNA,so immune complexes will develop, & wherever those immune complexesprecipitate at, theyre going to induce immune reactions.. in the kidney, joints,face, anywhere),, so those immune complexes have to be cleared out by thecomplement. If the complement fails to do that, then this disease becomes sosevere.

The memberane Attack Complex (MAC)

Mainly the activation of MAC leads to lysis of cells: damage of cells, of course.

Starts with C3 activation, C5-C9 (C5, C6 , C7, C8 and C9). The activation of C9starts the holes in the plasmic membrane.Ring formation and pores.Complement inhibitors: 8 inhibitors exist.Deficiency leads to illness, & the illness because of off-activation, i.e., failureof our body to stop the reaction.Complement are species specific, so all members of the species have the same

complement components, we dont react against each others complement, butwe do when we got those from animals. (very important to remember that)Complement deficiency is sometimes due to consumption, we talked about that

yesterday, if you have excessive reaction where you have consumed lot ofcomplement, if you measure the complement youll see a clot so you have here tomake a decision whether this is genetic or over-consumed.Significance of CRP and ESR.

We talked about this group of proteins that bind to the surface of bacteria, theyhelp in the phagocytosis process, & we said that a specific example is the CRP thatincrease in amount when we have an inflammatory process whether the origin of it is

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infectious (viruses, bacteria) or autoimmune complexes & so on. So we follow-up theprogress of the inflammatory process by these indicators: CPR & ESR; when they gohigh, it means we have inflammatory process thats going on. If the patient isresponding to treatment, then these parameters will go down.

This is whats going on, whenC9 binds, it starts forming holes,complement components 5,6,7,8allow 9 to penetrate the targetcell membrane. Ring of C9molecules form a pore across thecell membrane, so leakage ofwater & electrolytes will takeplace & the cell is going to bedestroyed by C9. When the C9

gets activated, well go throughthe whole cascade, as we said.

As I said, the complement is so important for the clearance of bacterial infectionsas you see, how the complement acts as 1 st line of defense when you have forexample- gram negative bacteria enters your body, you dont have time for Igs todevelop & so on, so the alternative pathway will start. So the complement here startsto be activated, they call upon for the macrophages to come into the area &phagocytose the bacteria that have invaded before even Igs develop. The alternativepathway can help into that, & then they can activate B cells as well at the same time tostart the process of Ig production & the other mechanisms are going to follow.

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The same thing here, the cytokines, the CRP & so on, or the inflammatory process

plays a major role & we said that the macrophages are of the innate system, those areso important & they give us the signal to the lymphocytes that may have been invaded.So when we get invaded by bacteria & so on as you can see here-, lymphokines &cytokines start to be produced & those can activate natural killer cells for example-& macrophages, they can destroy the infected cells by many different pathways.

Youll know more about the killing mechanisms thats going to be involved with thephagocytes & the killer cells, like the NK cells. And how these NK cells & macrophagescan also get activated by what comes out from the macrophages as the 1 st signal, theIFNs as well, & the more expression of MHC-I antigens. Ill tell you about the

relationship between the natural killer cells & the T-cytotoxic cells & how they differfrom each other & -of course- the role of the antigen presenting cells themacrophages- not just by phagocytosis & killing, & how those cytokines that areproduced from macrophages (like IL-1, TNF, IL-6, & IL-8) those they play a majorrole in the activation process & giving signals to the specific immune response callingupon for the neutrophils to come into the area. So what really cause the neutrophilswhen we are invaded, macrophages come & phagocytose, they produce cytokines (IL-8,, well talk about it in just a second ). IL-8 here can call upon neutrophils to come into thearea. So well tell you more about the role of APC in the cytokines that will be given tothe T-helper cell, so the innate immune system will give a danger signal to the specificimmune response that we have been attack.

The APR, INFs, the temperature that goes up because of IL-1,, all of that help indefending against invaders in general.

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And these are the pathways & theregulatory mechanisms that wevetalked about, the role of the C1inhibitor which is a soluble proteinthat cleaves C1 activating C4 & C2 &stop at this level. Also we have aseries of soluble & membrane boundinhibitors: decay activating factor,C4 binding protein, CR1. They alsoprevent the formation of C3convertase, prevent C3 activation(especially by the alternativepathway), & at the level ofalternative pathway we talked aboutthe factor H & I in the regulationprocess, & at the level of MAC theCD59 or the His protein that bindson the C5b, 6, & 7. And then theprocess will stop at this stage.

And here you can seethe relationship betweenpulse & temperature(sometimes the bloodpressure) & how when weare infected & themacrophages produce theIL-1 (which we call theendogenous pyrogen) &TNF, re-setup of ourhypothalamus & ourtemperature goes up.When the bodys temperature goes up, all the metabolic activities increase, &sometimes temperature is not suitable for so many microorganisms to grow & this isgoing to defend us against infection. Also we see when temperature goes up, our pulsewill go up, so hemodynamically the heart rate will go up & the process becomes soactive.

And well see how the phagocytosis can help in the production of nitric oxide. Nitricoxide makes vasodilatation, so lots of blood will be poured into the area & our bloodpressure starts to get down, so when we have massive infection, endotoxic shock, ourblood pressure goes down because of these mediators that come out of the

macrophages (especially the nitric oxide). & well tell you more about those.

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So you have to know the relationship between temperature & pulse: every time ourtemperature goes up, our pulse also will go up. I think by each degree, 10 pulses can beincreased.

Those are the APRs that we said. Look at day 1, at 12:00 AM for example-: theESR was 12, CRP was 4, the neutrophil count 5.1 X 10 3. On day 2: ESR almost triple &the CRP shooted up to 122 while neutrophils increased to 13.4 X 10 3. So you can seethe relationship between the APRs & how we can use those as markers of inflammationin general. And when you treat the patient, what you need to do is just to repeat theESR & CRP, & youll see how they start getting down when patient is in the recoveryphase.

So these APRs & the signals thatcome from the macrophages, theyare so important as nonspecificinnate immune defenses. So here for example- when were attackedby microorganisms, these are themacrophages, theyre producing theendogenous pyrogens (IL-1, IL-6,TNF) as I said , & those can affectthe hypothalamus raising ourtemperature up.

And remember that- youll learnnot to reduce our bodytemperature unless it goes beyond38.5 C. & the only thing you can dois just enhance the patient to havehis/her clothes off, use cold

compressors & so on, & we dont liketo use anti-pyretics, because the anti-pyretics (like the paracetamol, aspirin & so on)lower the setup of our hypothalamus, & we dont want that to happen, we want ourtemperature to be a little bit high, & we feel bad & tired & so on because of the APR(IL-1, 6 & TNF).. those what make us feel tired. So just let the temperature not gobeyond 38.5. If you remember, the normal body temperature is a range that variesfrom the early morning (around 36.5 almost) & the afternoon (maybe at 4:00 PM, cango up to 37.6). so we say that temperature [fever] starts from 37.7. this is the normalrange of our temperature [36.5-37.6], so we can let it go if the patient has fever upto 38.5, & at 38.5 we start to interfere: lowering the body temperature as I said-take the clothes off & use colds compressors. Reduce the temperature naturally!

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We dont like to give anti-pyretics, remember that! Dont give the child paracetamol(or any other anti-pyretic) immediately when temperature goes up, No! Let the normaldefenses play their role in defense.

And also the liver is going to be stimulated by these mediators to produce the CRPthat will help in the phagocytosis process & so on.

And as I told you, if you havedeficiency in the complement,

you become susceptible tobacterial infections. Look here for example-, these small cellsare PMNs (polymorphonuclearleukocytes - neutrophils). Thoseneutrophils come to the area bychemotactic factors. If you lookcarefully here, these small dots [at top of arrows] are gram negative diblococci, theseare N. meningitides. So this patient is infected with it. So you can see the intracellular& extracellular diplococcic, it happens in a patient who has a genetic deficiency withone of the complement components of the MAC, so patient become susceptible tobacterial infections; pyogenic type of infection.

So this is a summary ofwhat I was talking about, &

what happens when I have adefect in any part of thecomplement cascade leads toinfection -in general-,whether the MBL, theclassical pathway, or thealternative pathway, or at theMAC. Defects in the MAClead to recurrent neisserialinfections.

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This is what I told you about the angioneurotic edema. This is [on the left] thepatient normally. Because this patient has C1 inhibitor deficiency, minor trauma orminor infection will lead to severe type of reaction as you can see here [on the right]:edema all over, you start noticing that on the lips, look at his eyes & so on. Because ofthe excessive production of C3a & C5a & the activation of the kinin pathway as well, so

you see lots of edema, fluid in the tissue, contraction of the smooth muscles (byhistamines & others) through the activation of mast cells. [Next, the dr. is talking about a

case in KAUH]And this is what really happened with the patient died 3 weeks ago in theoperating theatre where they were trying to do brachioectomy to open the airway &they fail because of the severe contraction of the smooth muscle that patient washaving, & that patient had a very short neck, they couldnt even get into the neck toopen the airway. So remember that- how you can save the patients life by replacingthe C1 inhibitor, get fresh frozen plasma that is rich with C1 inhibitor & get a verylarge dose of corticosteroids. Corticosteroids can stimulate the body to produce C1inhibitor. It depends on the degree at which you receive these cases, most casesrecover & respond to treatment, i.e., rarely those patients die, but they die because

of suffocation & edema!

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PHAGOCYTOSIS

So well continue with the innate immune system, & well proceed with thephagocytosis process. You know, the 2 nd line of defense when were invaded, crossingthrough the 1 st line of defense (the skin & physical barriers & mucus membranes -mucus). Anything that gets into the circulation, we have the APR, complement,nonspecific, fever, & then we have phagocytic cells. When we talk about thephagocytic cells, mainly were talking about neutrophils & macrophages, those are themain phagocytes.

We should know that theres a difference between neutrophils & macrophages:macrophages have a longer half life & they can have other functions: antigenpresentation, production of APRs (IL-1, IL-6, TNF), chronic inflammation. When wehave chronic inflammation, we have macrophages. When we have acute inflammation,we have neutrophils. I want you to remember that as a start & well keep telling you that :

- When you have pus, were talking about neutrophils.

- When you have granuloma, chronic infections macrophages.

So we start with neutrophils, pus, acute type of inflammation. Macrophageschronic infections like Mycobacterium tuberculosis & others.

The outcome of phagocytosis: Recognition of pathogens, processing, presentation, &killing of course!

The macrophages in order to kill- require activation. The activation comes from thecytokines. Ill tell you more about this beautiful process.

Phagocytosis Definition:Simply, the engulfment & killing of bacteria, viruses, or foreign cells (in general). Thephagocytic cells have to be called upon into the area (chemotaxis), then the organism(or cell) has to bind to the surface, & then they have to be taken inside, & inside wehave the lysosomes that have to fuse with the phagosome to form the phagolysosome,& then a chemical reaction occurs inside (we call it the respiratory burst) that will killthe engulfed microorganisms, then the neutrophil will die to form a pus cell, while forexample- the macrophage will continue this process. Very important to remember that!

Triggering factors of phagocytosis:

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Inflammation, infection, injury, chemotactic factors, complement activation, IL-8production, calling upon these phagocytic cells to come into the area.

Very important point: neutrophils are not present normally in tissues [repeated twice toindicate its importance!] , they have to be called upon to come into the area. When you seeneutrophils in the CSF, definitely you have a bacterial infection, because normally inCSF we dont see neutrophils. While for example- in tissues, we have macrophages!

Structure related to function:

So what do we have inside the neutrophils & the macrophages? We have granules, &those granules have enzymes, & the enzymes mediate biochemical reactions, & thesebiochemical reactions lead finally killing & death of the organism that has beeningested in a process we call it the respiratory burst.

Respiratory burst (the hexose monophosphate shunt pathway):

Where the enzymes that are present inside (like the myeloperoxidase enzyme - the

main one) lead to the production of superoxide anions, free radicals, hydroxyradicals,hypochloride anions that will severely oxidise these types of microorganisms, & so on.

The outcome of phagocytosis :

Clearing out bacteria, protozoa, fungi, and any cell debris, i.e., like scavengers.

So these are the phagocytic cells:

[a]: Here you can see the neutrophils, they have more than one nuclei [to be

specific: its segmented nucleus], you can see the granules inside, & those granules willlead to the respiratory burst, & -in fact- when we look at it under the microscope, wesee the segmentation of the nucleus.

[b]: here you can see the macrophages, kidney-shaped nucleus that is much largerthan the neutrophil in a way, & has granules as well.

[c]: when it [macrophage] becomes activated, you see lots of granules increase inside,it becomes nucleated we call them multinucleated giant cells or epitheloid cells. Sowhen you hear the term multinucleated giant cells / epitheloid cells, this means

activated macrophages, activated by the IFNs. Macrophages are highly killing

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compared to neutrophils [or non-activated macrophages .. the idea wasnt so clear, but both arecorrect! ..] .

So neutrophils are the most common phagocytic cells that we have. Theyre presentin a very large number, they come out of the bone marrow under the influence of IL-3first, & then later IL-8.

IL-3 increases hematopoisis in bone marrow in general. While IL-8 helps in thedifferentiation of those into neutrophils. Our bone marrow produces almost 10 9 cellper day, imagine! Each cell has a half life of about 6 hours only. While themacrophages are more efficient, they stay in our body for a longer period of time,they dont get expired by the act.

Neutrophils are most numerous, they travel, kill, & then get killed. We call them puscells. So, if we have few number of neutrophils, we call that neutropenia. If wereneutropenic, we become immune compromised because the ability to phagocytose & killwill be less. Neutropenia leads to pyogenic type of infection. We become neutropeniceither genetically (by defect of certain enzyme) or our bone marrow is exposed toradiation or drugs so it will not produce that many of neutrophils. So if the somebodyhas a serious recurrent bacterial infection, then the patient is immune compromised the patient is usually neutropenic.

One of the tests that we do to check immune competency is to see the number ofneutrophils. If the number is normal & we still have bacterial infection, this meansthat neutrophils dont function; theyre normal in number but not functioning thatmeans some of the enzymes are deficient, like in chronic granulomatous disease or

Chediak Higashi syndrome & so on.* Neutrophils Macrophages

1 Rapid increase in production duringthe acute

Slight increase in blood levels during inflammationphase response

2 Only found in inflamed tissues Found in healthy tissues3 Single mature form Variety of mature forms4 Rapidly form pus Slowly form granuloma with T-cell help5 Short lived die after phagocytosis Long lived survive after phagocytosisThese are some differences between neutrophils & macrophages. [The dr. just read the

table, so study it! I reprint it to be more clear when copied on papers..] . Some notes:- The 2 nd difference is extremely important difference.- Macrophages are called according to the location where theyre present:

Stay completely in the blood monocytes. Brain oligoglial cells / glial cells Kidney mesangial cells [btw, the dr. repeated it twice & in both sound like

mesenchymal, but on Wikipedia its intraglomerular mesangial just 2 be honest!] Connective tissue histiocytes

Bone osteoclasts Skin langerhans cells

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Liver Kupffer cells Alveoli (lungs) alveolar macrophages & when they are activated multinucleated giant cells

All of those are different names for macrophages that I want you to remember. Itdepends on their location.

So if I want to have efficient phagocytosis, I need very high number of neutrophilsto come into the area.So the monocytes/macrophages myeloid cells as you know-, then they migrate from

the bone marrow to tissues, & in the tissues we call them by the names Ive justmentioned. Their life span is much longer than neutrophils.

Tissue macrophages have specialized granules. We call them histiocytes.

** Giant and epitheloid cells: activated macrophages in chronic inflammation. They getactivated because of the cytokines; mainly were talking about IFN- , very importantto remember that! It forms granuloma (for example, the thickening that we see onthe skin or in the kidney or lungs, that destroy the tissue that they have). Granulomais formed of activated macrophages, no pus! We see pus in acute infections neutrophils.

** Fixed macrophages: in the spleen and liver (Kupffer cells). They can phagocytosewhole cell.

So this is how they developed & how they get distributed, start from the

hematopoietic stem cells (CD34) & then how they differentiate into lymphoid series &myeloid series (including red blood cells). They require cytokines & growth factors like

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granulcyte-monocyte colony stimulating factor (GM-CSF). So the granulocyteprecursor will give you the neutrophils & eosinophils under IL-8 & IL-5. Then IL-4 willmake the cell [CD34] differentiate into mast cell (& IgE Abs will be produced) &monocyte/macrophage that will come here to be distributed in tissues to be tissuemacrophages (histiocytes, epitheloid, multinucleated giant cells activatedmacrophages), fixed macrophages in the spleen, liver (Kupffer cells), & alveoli (alveolarmacrophages).

(: .!. BEST WISHES 2 ALL & BLESSED RAMADAN :D .!. :)