30 17

Complement (cont.) & Phagocytosis

Aisha Gharaibeh Ziad Elnasser Tuesday, 26/7/2011

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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 CR = Complement Receptor EBV = Epstein-Barr Virus Ig = Immunoglobulin IFN = Interferon MAC = Membrane Attack Complex RBC = Red Blood Cell APR = Acute Phase Response CRP = C-reactive protein ESR = Erythrocyte Sedimentation rate IL = Interleukin NK cells = Natural Killer cells MBL = Mannan Binding Lectin TNF = Tumor Necrosis Factor

Announcements by Dr. Elnasser:

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Well have the 2nd midterm exam on 13th of August. Next week will be Ramadan, so HAPPY RAMADAN . I hope you looked at the new schedule & see the new timetable, so our class will start at 10:00 AM rather than 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 complement activation is destruction of cells where the complement is fixed on its surface. 2nd component of the complement -like C3a, C5a- act as anaphylatoxins, so they stimulate mast cells & basophils so release their vasoactive amines so we'll see inflammation associated with that. Those two [C3a & C5a] act as chemotactic factors, they call upon phagocytic 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 the phagocytosis process in what we call opsonisation (the property related to Igs the IgG type- & the receptor of the IgG, so IgGs are opsonins), the same thing in the complement, C3b can act as a complement as well.. so you have both (Ab & the complement) & 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 that these immune complexes will stay in our body & will inflict injury, like systemic lupus erythromatosus (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. Those 2 [C4 & C2] are going to be splitted into smaller components & larger components. The smaller components have other functions, for example, C2a activates the kinin pathway, & 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 the C3 convertase, so the C3 convertase acts on C3, splitting that into C3a & C3b. so C3a acts as anaphylatoxin & chemotactic factor. C3b binds to the surface of the cell to form what we call C5 convertase, so we have 4b2a3b, form this C5 convertase to split C5 to C5a & C5b. C5b binds to the surface & starts the process of what we call the membrane attack complex. So the membrane attack complex starts with C5b which binds & activates C6 binds & actives C7, so C5b67 activates C8. C5b678 starts the process initially of making holes in the cytoplasmic membrane but the real hole occurs when C9 gets activated & joins so a major leak is going to take place in the cytoplasmic membrane & 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 inhibitor binds to the C1q preventing its activation & so no C1r will be activated & the process will stop. We said that if C1 inhibitor is missing then the patient is going to have a disease we call it angioneurotic edema where any minor infection or trauma (sometimes psychological cause or unknown cause) then the reaction keeps going on & on, & all the components are going to activate the mast cells & basophils & well have lots of inflammatory mediators, & edema is going to develop, & lots of tissue, & kinin cascade will 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 to decay activating factor, co-factor of the cytoplasmic membrane, CR1 also, so all of them 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 preventing the activation of C8 so itll stop & the reaction here will not take place. And we said that if we have any deficiency of the complement components then were going to become immune compromised. And they have noticed that if they have deficiency of any of the components of the MAC. For example, people become more susceptible for pyogenic 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 in defense of those types of infections & how if any of those complement deficiencies at a higher level also then immune complexes cannot be cleared up & you develop autoimmune diseases, like systemic lupus erythromatosus & so on. So its so important to know about complement & its activation, & we said that C3 has the highest concentration in serum & it makes sense because in the pivot where all the 3 pathways end up. The alternative pathway starts at C3. We said what activates the classical pathway is 2 IgGs or 1 IgM, while in the alternative pathway its lippolysaccharide of bacteria activates C3 which is splitted into C3a & C3b. C3b binds to the surface & it depends whether the surface is self or nonself: if its nonself then factor B will bind, the minute factor B is bound itll be hit by factor D splitting the factor P into smaller components: Ba & leaves behind the bigger component Bb. So we have C3bBb, this is what 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 then C3 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 to form 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 is going to bind so now we have C3bH which is going to be hit by factor I (inactivating factor) destroying C3b into inactive C3b. And those have receptors on cells as well at the same time & the reaction will stop. This is how the alternative pathway is regulated. Then we talked about the MBL where the mannan-binding starts here by the activation of C4 & then C2 & the processes go to C3 like those in the classical pathway. The only difference is that we dont have C1 & mannan-binding here activates this 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 the

alveoli- binds to carbohydrates of the bacteria & activates C4, C2, & then C3. & 2 IgGs, start with C4 then C2 then C3
important!),

- Classical pathway: immune complexes, Ag-Ab reaction, starts with C1, you need IgM - Alternative pathway: starts directly on C3, we dont have C1 or C2 or C4 (this is really

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 the complement. The complement components are inactive unless theyre cleaved. When they start to become cleaved they become active. And then the last fragment has enzymatic activity binds to the surface, the smaller components -like C3a, C4b, C5ago & act as anaphylatoxins & chemotactic factors, so they bind to the surface unless theyre blocked by an inhibitor as we said.

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

Once one component is activated it will activate downstream components, this is

what 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 responsible

for the inflammation that we see when the complement is activated.

This is here how the complement mediates the inflammation, & you see how these white blood cells will come out from the blood vessels into the area by chemotactic factors. Anaphylatoxins increase the vessels permeability, leukocyte adhesion is increased & then they will pass into the area. When leukocytes reach tissue, anaphylatoxins stimulate phagocytosis & degranulation will take place.

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And we said also that complement can clear out immune complexes as you can see. They can first activate phagocytes, they act as opsonins. So you can see here, we have a receptor on the surface of a macrophage, the receptor binds the complement, & a complement is bound here to immune complex so itll be taken inside, it helps in the phagocytosis. Also complement can activate B cells (& we talked about that before), if you remember the complement receptor 2, the CD21 (which is the target of the EBV) can act as receptor for the activation process & also clearance of immune complexes whether those are insoluble or soluble, insoluble immune complexes may form in the tissue, complement binds Ig FC portions, so you can see how complement 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 the complement, so when you have an immune complex that binds to the surface of the RBC, RBC can carry those immune complexes in the circulation & clear those immune complexes in the spleen. A complement binds to receptor on RBCs which transport immune 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 complement components, 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 could

have C4a as well in smaller proportion.

CRs In order for those to work, we must have receptors for those complement components on cells. The MBL, C1, C4, C3. And when we talk about CRs, we talk about 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 have a receptor for IgG on the surface of the phagocytic cell, so IgG blocks by its place, so the binding site will be cleared so the organism will bind to the attachment sites of the Ig & itll be taken in. The same thing with the complement, has C3b receptors, so the C3b on the surface of the bacteria will bind to its receptor & we have both (the IgM & the complement), then the phagocytosis 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 Soluble because of the complement (C4 and C3) bind to surfaces of RBCs & fix macrophages. If complement is deficient, clearance of those immune complexes is 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 complexes precipitate at, theyre going to induce immune reactions.. in the kidney, joints, face, anywhere),, so those immune complexes have to be cleared out by the complement. If the complement fails to do that, then this disease becomes so severe.

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 C9

starts 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., failure of 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, but we do when we got those from animals. (very important to remember that)
yesterday,

Complement deficiency is sometimes due to consumption, we talked about that

if you have excessive reaction where you have consumed lot of complement, if you measure the complement youll see a clot so you have here to make 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, they help in the phagocytosis process, & we said that a specific example is the CRP that increase 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 the progress of the inflammatory process by these indicators: CPR & ESR; when they go high, it means we have inflammatory process thats going on. If the patient is responding to treatment, then these parameters will go down. This is whats going on, when C9 binds, it starts forming holes, complement components 5,6,7,8 allow 9 to penetrate the target cell membrane. Ring of C9 molecules form a pore across the cell membrane, so leakage of water & electrolytes will take place & the cell is going to be destroyed by C9. When the C9 gets activated, well go through the whole cascade, as we said.

As I said, the complement is so important for the clearance of bacterial infections as you see, how the complement acts as 1st line of defense when you have for example- gram negative bacteria enters your body, you dont have time for Igs to develop & so on, so the alternative pathway will start. So the complement here starts to be activated, they call upon for the macrophages to come into the area & phagocytose the bacteria that have invaded before even Igs develop. The alternative pathway can help into that, & then they can activate B cells as well at the same time to start 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 are so 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 the phagocytes & the killer cells, like the NK cells. And how these NK cells & macrophages can also get activated by what comes out from the macrophages as the 1st signal, the IFNs 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 differ from each other & -of course- the role of the antigen presenting cells the macrophages- not just by phagocytosis & killing, & how those cytokines that are produced from macrophages (like IL-1, TNF, IL-6, & IL-8) those they play a major role in the activation process & giving signals to the specific immune response calling upon for the neutrophils to come into the area. So what really cause the neutrophils when we are invaded, macrophages come & phagocytose, they produce cytokines (IL8,, well talk about it in just a second). IL-8 here can call upon neutrophils to come into the area. So well tell you more about the role of APC in the cytokines that will be given to the T-helper cell, so the innate immune system will give a danger signal to the specific immune response that we have been attack. The APR, INFs, the temperature that goes up because of IL-1,, all of that help in defending against invaders in general.

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And these are the pathways & the regulatory mechanisms that weve talked about, the role of the C1 inhibitor which is a soluble protein that cleaves C1 activating C4 & C2 & stop at this level. Also we have a series of soluble & membrane bound inhibitors: decay activating factor, C4 binding protein, CR1. They also prevent the formation of C3 convertase, prevent C3 activation (especially by the alternative pathway), & at the level of alternative pathway we talked about the factor H & I in the regulation process, & at the level of MAC the CD59 or the His protein that binds on the C5b, 6, & 7. And then the process will stop at this stage. And here you can see the relationship between pulse & temperature (sometimes the blood pressure) & how when we are infected & the macrophages produce the IL-1 (which we call the endogenous pyrogen) & TNF, re-setup of our hypothalamus & our temperature 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 is going to defend us against infection. Also we see when temperature goes up, our pulse will go up, so hemodynamically the heart rate will go up & the process becomes so active. And well see how the phagocytosis can help in the production of nitric oxide. Nitric oxide makes vasodilatation, so lots of blood will be poured into the area & our blood pressure starts to get down, so when we have massive infection, endotoxic shock, our blood 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 our temperature goes up, our pulse also will go up. I think by each degree, 10 pulses can be increased.

Those are the APRs that we said. Look at day 1, at 12:00 AM for example-: the ESR was 12, CRP was 4, the neutrophil count 5.1 X 103. On day 2: ESR almost triple & the CRP shooted up to 122 while neutrophils increased to 13.4 X 103. So you can see the relationship between the APRs & how we can use those as markers of inflammation in general. And when you treat the patient, what you need to do is just to repeat the ESR & CRP, & youll see how they start getting down when patient is in the recovery phase. So these APRs & the signals that come from the macrophages, they are so important as nonspecific innate immune defenses. So here for example- when were attacked by microorganisms, these are the macrophages, theyre producing the endogenous pyrogens (IL-1, IL-6, TNF) as I said, & those can affect the hypothalamus raising our temperature up. And remember that- youll learn not to reduce our body temperature unless it goes beyond 38.5 C. & the only thing you can do is just enhance the patient to have his/her clothes off, use cold compressors & so on, & we dont like to 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 our temperature 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 go beyond 38.5. If you remember, the normal body temperature is a range that varies from the early morning (around 36.5 almost) & the afternoon (maybe at 4:00 PM, can go up to 37.6). so we say that temperature [fever] starts from 37.7. this is the normal range of our temperature [36.5-37.6], so we can let it go if the patient has fever up to 38.5, & at 38.5 we start to interfere: lowering the body temperature as I saidtake 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 normal defenses play their role in defense. And also the liver is going to be stimulated by these mediators to produce the CRP that will help in the phagocytosis process & so on. And as I told you, if you have deficiency in the complement, you become susceptible to bacterial infections. Look here for example-, these small cells are PMNs (polymorphonuclear leukocytes - neutrophils). Those neutrophils come to the area by chemotactic factors. If you look carefully here, these small dots [at top of arrows] are gram negative diblococci, these are 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 with one of the complement components of the MAC, so patient become susceptible to bacterial infections; pyogenic type of infection. So this is a summary of what I was talking about, & what happens when I have a defect in any part of the complement cascade leads to infection -in general-, whether the MBL, the classical pathway, or the alternative pathway, or at the MAC. Defects in the MAC lead to recurrent neisserial infections.

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This is what I told you about the angioneurotic edema. This is [on the left] the patient normally. Because this patient has C1 inhibitor deficiency, minor trauma or minor 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 of the 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 (by histamines & 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 the operating 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 was having, & that patient had a very short neck, they couldnt even get into the neck to open the airway. So remember that- how you can save the patients life by replacing the C1 inhibitor, get fresh frozen plasma that is rich with C1 inhibitor & get a very large dose of corticosteroids. Corticosteroids can stimulate the body to produce C1 inhibitor. It depends on the degree at which you receive these cases, most cases recover & 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 the phagocytosis process. You know, the 2nd line of defense when were invaded, crossing through the 1st 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 the phagocytic cells, mainly were talking about neutrophils & macrophages, those are the main phagocytes. We should know that theres a difference between neutrophils & macrophages: macrophages have a longer half life & they can have other functions: antigen presentation, production of APRs (IL-1, IL-6, TNF), chronic inflammation. When we have 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:
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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. Macrophages chronic 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 the cytokines. Ill tell you more about this beautiful process. Phagocytosis Definition: Simply, the engulfment & killing of bacteria, viruses, or foreign cells (in general). The phagocytic 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 we have 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 kill the engulfed microorganisms, then the neutrophil will die to form a pus cell, while for example- 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-8 production, calling upon these phagocytic cells to come into the area. Very important point: neutrophils are not present normally in tissues [repeated twice to indicate its importance!], they have to be called upon to come into the area. When you see neutrophils in the CSF, definitely you have a bacterial infection, because normally in CSF 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, & these biochemical reactions lead finally killing & death of the organism that has been ingested 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 will lead to the respiratory burst, & -in fact- when we look at it under the microscope, we see the segmentation of the nucleus. [b]: here you can see the macrophages, kidney-shaped nucleus that is much larger than 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. So when 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 are correct! ..]. So neutrophils are the most common phagocytic cells that we have. Theyre present in a very large number, they come out of the bone marrow under the influence of IL-3 first, & then later IL-8. IL-3 increases hematopoisis in bone marrow in general. While IL-8 helps in the differentiation of those into neutrophils. Our bone marrow produces almost 109 cell per day, imagine! Each cell has a half life of about 6 hours only. While the macrophages 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 pus cells. So, if we have few number of neutrophils, we call that neutropenia. If were neutropenic, we become immune compromised because the ability to phagocytose & kill will be less. Neutropenia leads to pyogenic type of infection. We become neutropenic either genetically (by defect of certain enzyme) or our bone marrow is exposed to radiation or drugs so it will not produce that many of neutrophils. So if the somebody has 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 of neutrophils. If the number is normal & we still have bacterial infection, this means that neutrophils dont function; theyre normal in number but not functioning that means some of the enzymes are deficient, like in chronic granulomatous disease or Chediak Higashi syndrome & so on.
* 1 2 3 4 5 Neutrophils Rapid increase in production during the acute Only found in inflamed tissues Single mature form Rapidly form pus Short lived die after phagocytosis Macrophages Slight increase in blood levels during inflammation phase response Found in healthy tissues Variety of mature forms Slowly form granuloma with T-cell help Long lived survive after phagocytosis

These 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:
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The 2nd 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 Connective tissue histiocytes Bone osteoclasts Skin langerhans cells
mesenchymal, but on Wikipedia its intraglomerular mesangial just 2 be honest!]

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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. It depends on their location. So if I want to have efficient phagocytosis, I need very high number of neutrophils to 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 just mentioned. 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 get activated because of the cytokines; mainly were talking about IFN-, very important to remember that! It forms granuloma (for example, the thickening that we see on the skin or in the kidney or lungs, that destroy the tissue that they have). Granuloma is formed of activated macrophages, no pus! We see pus in acute infections neutrophils. ** Fixed macrophages: in the spleen and liver (Kupffer cells). They can phagocytose whole 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 granulocyte precursor will give you the neutrophils & eosinophils under IL-8 & IL-5. Then IL-4 will make 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 tissue macrophages (histiocytes, epitheloid, multinucleated giant cells activated macrophages), fixed macrophages in the spleen, liver (Kupffer cells), & alveoli (alveolar macrophages).

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

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