Secondary Immunodeficiencies (Part 1 of 2) PDF

Okey-dokey, hi all. We left off last class with our 88 deficiency here, which is part of that group 1 disorder here. And so we move in, and actually I'm gonna make this a little bit bigger so you guys can see. And so when you have defects in T-cell numbers, this will result in abnormal numbers or...

Okey-dokey, hi all. We left off last class with our 88 deficiency here, which is part of that group 1 disorder here. And so we move in, and actually I'm gonna make this a little bit bigger so you guys can see. And so when you have defects in T-cell numbers, this will result in abnormal numbers or function, or and or function overall. So you could have abnormal numbers, but normal function, or normal numbers, but abnormal function, or both. And it can affect either CD4 or CD8 T-cells, or both. And what you'll see with patients who have is they'll have frequent or recurrent fungal infections that will suggest a T-cell defect because delayed type hypersensitivity, so DTH, I should have spelled that one out. In previous years I'd presented the hypersensitivity lecture before this, but we will cover delayed type hypersensitivity lectures, or terms in the future, so, but DTH means delayed type hypersensitivity, and it is largely responsible for the clearance of fungi and infections specifically. And so you can have mutations that occur in critical cells to development or activation, so multiple different things can lead to this. And there are a couple different examples that we'll talk about, and these guys are ones to know since they were included in your learning objectives. So again, I did mention, you know, those charts, I'm not going to go through a nitpicky, like, make you memorize everything from the charts, but there are still specific disorders you do have to know. And one of them is TAP deficiency, or TAP deficiency. It's also known as Bayer lymphocyte syndrome because it's due to a defect in the transporter associated with antigen processing known as TAP. You guys might remember that one. And so because of that, and I remember that from module two, an antigen presentation, because of that it will impair the loading of peptide fragments in MHC class 1 in all nucleated cells, and therefore it reduces the number of MHC1 molecules that reaches the surface, so you don't see MHC molecules on the surface giving you, you know, this Bayer lymphocyte syndrome because, you know, the cells look like they don't have any receptors on their surface. And that's why they kind of got that nickname here, but it's due to a TAP deficiency. And so you'll have, with reduced MHC expression, decreases in the number of functional CD8 to T cells, and it can also affect the functions of effects. MHC class 2, this would be the same, but with CD4 cells specifically do the rule of eight. So it does affect the ability to load peptides and MHC and MHC processing in general, and so you won't see as many MHC molecules on the surface that's leading to that Bayer lymphocyte syndrome. You also have the George syndrome, which is where you have a defect in thymic development overall, and because of that, that may inhibit or prevent development in thymic education of T cells, because if you damage the thymus, you know, T cells don't have a school to go to. It is variable in severity depending on the original cause of it, and it can also include physical malformations so that you could see it on an infant, where you could have malformations of an aorta and not for the heart. There can also be face or jaw malformations, where the face or jaw is a little bit different, as well as changes to the parathyroid glands overall. Due to the symptoms, overall and early testing do help us with early detection and treatment at birth, and so, you know, there can be supplementation, things like that, to try to help treat this overall here, too. I do want to flag that if you look at the charts very carefully, DeGeorge is actually classified under group 2 now, but just where this is in the lecture, I'm going to keep it here, and so I won't be, you know, nitpicking and asking if DeGeorge is under 1 or 2, I just put this note here because I do want to keep it simplistic and learning, but it does fall under group 2, not just to know, as an aside, if you go into pediatrics or rare developmental diseases, and that's why it kind of ties into this one here. When you have combined immunodeficiencies with associated syndromic features, and that's why DeGeorge falls under here, too, because if you look at the symptoms, it does affect, you know, the aorta, face, jaw, parathyroid glands, that's why we kind of originally classified it here. You know, kind of originally before we had a really good grouping system, we did kind of separate them based on whether they affect T cells or B cells, things like that, but now we're learning it's a little bit more complicated, and that's, you know, the charts that we see here are the most recent updates in terms of organization and diagnostic criteria, the different disorders here. But group 2 are combined immunodeficiencies with associated or syndromic features, and so defects in T cell function underlie several of these severe combined immunodeficiencies here, and so that's why we do have, you know, the DeGeorge here. You see it's listed under thymic defects here, and so again, you know, originally classified kind of in the beginning, but again, because it affects T cells and that's why I just kind of listed all T cells here, you know, I do split it between that one and here, but I won't be, you know, nitpicky or asking an unfair question on the exam due to that specifically. And we talked about some other examples of those combined immunodeficiency disorders. Wiscott Aldridge is a very commonly tested one on boards, even though it is a rare X-linked recessive immunodeficiency disorder, resulting in abnormal immune function and reduced ability to form blood clots. With this one, this is a critical one, though, because life expectancy is about 3.5 months without treatment, so very quickly after birth it is a possibility to die from this without treatment. And a good way of remembering Wiscott Aldridge is the acronym WATER because Wiscott Aldridge, W-A, but you can also think about it in that it affects the WAS gene or W-A-S gene mutations that get to the W-A of WATER. You see thrombocytopenia with it, so decreased platelets overall here, or they can be very, very small, so they're ineffective here. You can also see eczema with it, or atopic dermatitis, and recurrent bacterial infections here due to the problem with the immune system overall, and it's due to that WAS gene mutation overall. And so you also have ataxia telangiectasia, also known as Lewis-Barr syndrome. This is a rare inherited childhood neurological disorder that will affect part of the brain that controls motor movement and speech. Patients do have an increased risk of leukemia and chronic lung conditions due to this, so we get its name because ataxia means without coordination, and so that's why, you know, again, it's a part of the brain that affects motor movement and speech, and so they can walk or crawl a little funny because they don't have coordination here. And telangiectasias are small, widened blood vessels on the skin, so you'll have these tiny flat red marks that will appear on the skin as a consequence of this, and so that's like, you know, the very scientific name of it, but it was also known as Lewis-Barr based on people who discovered it and experienced it here. Most patients who have this become wheelchair bound by about 10 years old and generally die in their 20s or 30s, obviously due to malignancies like the increased risk of leukemia, as well as respiratory insufficiency, so they are more susceptible to upper respiratory infections, things like COVID flu, things like that. And so, group three is predominantly affecting antibody deficiencies. If you have antibody deficiency, this can lead to poor clearing of extracellular bacteria. Think about all the different, you know, effector functions of antibodies, you know, depending on which antibody is affected, you know, if it's all of them, some of them, a few of them, you know, specific ones, can lead to different, you know, signs and presentations here. And so, obviously, if you have a chart like this, you know, I'd give you information, like, you know, a patient presents, you know, frequently getting bacterial infections or, you know, ear infections, sinusitis, diarrhea, sepsis, pneumonia, whatever, you know, and then you do blood work to do a serum immunoglobulin assay. And, you know, they had decreased IgA, IgG IgA and or IgM here. If they just had decreased IgG, decreased IgA and IgM is normal or elevated, falls under here, decreased IgA alone is here, or if they have normal all of these guys, but, you know, effector function is altered here, you know, we fall under this column here, and then also they're just learning just to do genetics that congenital B-cell lymphocytosis actually falls under here too, because, again, this will eventually, if you take out B-cells, eventually affect, you know, antibody production overall. So, a lot of these guys come from defects in B-cells overall, because as you guys know, B-cells are what differentiate into plasma cells to secrete antibodies. And B-cell defects actually are responsible for a majority over 80% of human immunodeficiency diseases, which I guess is kind of nice because then you kind of only take out, you know, one part of the immune system here. You still have functioning T-cells, usually you still have an innate immune system, you still have the ability to have complement pathways, minus the fact that you'll probably take out a classical complement pathway, since you can't produce antibodies, which activates the classical complement pathway, there's still backup, you know, mechanisms to keep the body safe. So, immunoglobulin levels are typically affected, but you may not always see changes in B-cell numbers. And so, you know, the B-cell count could be not a normal CBC, but if you do additional testing, you notice that immunoglobulin levels are affected. It can also be abnormal production of one or more, so it's supposed to be one plus immunoglobulin isotopes. So, like this previous chart shows, it could just be IgA, or it could be IgG, IgA, a normal or high IgM. So, there are various, you know, presentations that we hear too. The example specifically that I do want to know though, selective IgA deficiency, this is most common immunodeficiency, which is about one to two people are diagnosed per every 1,000 people, and I've actually had so far in all the years I've been teaching. So, I'd say it's probably, you know, 200, 300 students. I've had one student come forward who had selective IgA deficiency here. But usually with this, it's due to multiple gene defects that can produce it, and evidence that some forms may involve defective isotope switch signaling from T- cells. So, like the T-cells are not secreting the correct cytokines to tell those B-cells to switch to IgA specifically, which is kind of cool. As you guys know, that's how, you know, isotope switching occurs, and we get IgA. We frequently have normal levels of all other isotopes, and often have other immunological disorders though, like allergy and immunity. Because think about it, we do see IgA at mucosal areas, as well as pass on to an infant. So, there are other effects present, but we do frequently see other immunological disorders, like allergies or autoimmunity. And so, another one we'll talk about is immune deficiency with hyper IgM. So, that's where we got this H-I-G-M, hyper IgM here. Because you do have an immune deficiency overall, but this can, this is the defect in the CD40 ligand deficiency. It's, you know, one of the examples is immune deficiency with hyper IgM. Because the isotope switch does not occur normally, so you get high levels of IgM, because again, you haven't taken out the ability to produce immunoglobulin molecules in the beginning, but you will be deficient in B cells that produce IgG, A, or E. And so, basically, you have hyper increased IgM, because again, your body is able to produce immunoglobulin molecules. It just has issues with forming the switch. And so, that's due to, you know, not being able to have that germinal center where these guys can undergo isotope switching. So, it's really cool to kind of see that overall here, too. The other example we'll talk about, too, is X-linked Agammaglobulinemia, or X-L-A, here. And so, in X-LA, and you guys should know Bruton's tyrosine kinase, that was one of those things I had you guys memorize for this last exam with B cells. So, it is important to know that it is caused by Bruton's tyrosine kinase. You've also seen people call it Bruton's tyrosine kinase deficiency, but it's X-LA. And so, because of this, B cells do not develop beyond that pre-B cell stage, just due to B cells basically will become arrested at that pre-B cell stage, because the pre-B cell receptor cannot generate enough intracellular signaling in order to progress onwards here, too. We do know the BTK gene is located on the long arm of the X chromosome. And so, most people who actually have the physical presentation of X-LA are male, because again, they only have one X chromosome, and there's no BTK gene on the Y chromosome. For a female to express that they would have had to inherit two defective X chromosomes, so that's why it is a little bit more rare in females. So, you see a lot of heterozygous female carriers of the trait, because they have one defective X chromosome, but again, they need to inherit two copies in order to be able to present the disease. And so, when we talk about development in general, I don't know if you guys covered this with Dr. Ocel, cells in females will randomly inactivate one X chromosome, and so consequently, half of your developing B cells in a female carrier will become arrested at that pre-B cell stage, because those cells inactivated X chromosome had that good copy of the BTK. So, you can see like mild variation in women where they have like slight deficiencies, like again, it's taking out half of the B cells here, not the full amount as if you had a male who had inherited one defective chromosome here. The other half of developing B cells will become those functional B cells, because they inactivated the X chromosome that has the bad copy of BTK. And so, you know, there's a lot of different instances here, but in case you want to see the stages, you have a pro-B cell, pre-B cell, and immature B cell here. And this one is showing a normal male, so the X chromosome is not affected, it does have a BTK. You have an XLA male, so it's missing that BTK gene here, and you have the carrier of females. So, this is showing the two different possibilities here, where the defective X is inactivated, and this one where the normal X is inactivated. And so, it gives you two different examples with the females here. With the normal male, obviously, we test it. We use that pre-B cell receptor to make sure the heavy chain is fully functional, and if it is fully functional, that B cell is allowed to progress. It's not fully functional during this first test. Remember, it goes to apoptosis, and so with this one, we tested it. It was great, and so now it's showing that full heavy and light chain presented on the surface, and you have that, you know, IgM expressed in the surface of this immature B cell. Versus in a male that's missing that BTK deficiency, you know, you have this arrested pre-B cell stage, because we can't generate enough intracellular signals to allow it to progress, you know, due to that pre-B cell receptor here. And so, the B cell development will end up being arrested, and so, you know, they don't produce B cells as a consequence of this, and so, you know, they take out part of the immune system here. Now, when we talk about the females, the two different examples you can see, depending on which X is inactivated as we're going through development here, if you inactivate the defective X, you'll still go through and progress, because you're actually just knocking out the one that doesn't work, which is fantastic. It works out in our favor. We have fully present immunoglobulin molecules on the B cell here, versus if we end up inappropriately inactivating the X chromosome, unfortunately those cells will also get arrested, and so you won't be able to see that. And so, you can still see some presentation in carrier females, but again, you know, it's more dangerous if you've inherited both defective X genes, kind of, as you're going through it, too. When you talk about diminished production of antibodies can also arise from inherited defects in T cell help. Like we talked about, you know, the IGA deficiency, if you're not getting appropriate signals to tell the B cells to switch, things like that, you can affect B cells and immunoglobulin molecules as a downstream consequence here, and again, it's because those T cell help is critical to the activation of naive and memory B cells, so it can also cause abnormality in both B cell number and in immunoglobulin production overall. So that's just an important fact to take away of all those previous things that we looked at. When we talk about diseases of immune dysregulation, this means it's immune. Its ability to function is different, and so, you know, you can see a lot with lymphocytocytosis effects in your cells here, increases of, like, phagocytic of blood and stuff like that, which is interesting, of, like, red blood cells. You have autoimmunity syndromes associated with this. Also, immunosurregulation with colitis falls under its own category here. Like, you guys should recognize some of these terms, like IL-10, there's a deficiency in cytokine IL-10, which is pretty interesting, too, but a lot of different is, you know, for the most part genetic, but there are some pretty interesting, like, that's affecting the presence of CD25 on the surface of the cell. So a lot of different types of presentations, which is fascinating overall. Also, notice there's an ADA-2 over here. It is a slightly different disease presentation than the ADA that we saw before. that we saw before. And so, with group 5, this is congenital defects. Oh, and I do want to point out, this is all I want you to know for group 4. I didn't go through specific examples with these guys here. And so, you know, you might see something from the chart, or I might ask you, like, what falls under group 4? you, like, what falls under group 4? It's diseases of immune dysregulation, where they mean function is altered. So we're talking about group 5. This is congenital defects, a phagocyte number, function, or both. And so, defects and phagocytes also cause enhanced susceptibility to bacterial infections, because again, they're some of the first line of defense with bacterial infections overall. And so, this is showing those PMNs are polymorphonuclear cells, which are basically your neutrophils, as they have multi-shaped nuclei, polymorphonuclear cells. And sometimes you can see low levels of neutropenia with it. Sometimes you don't, things like that. And so, normal kind of would fall through here. And then we have other testing, so we can determine if it's abnormal or normal here. There's a lot of different varieties here, but again, you would be given information on how to go through and read. You know, I provide information and tell you, like, yes, there's PMN, and it looks like that. So, when you take out the phagocytes, notice again, you're knocking out that phagocytic, or I'm sorry, monocyte lineage over here, so that can affect your monocytes and your dendritic cells and your macrophages and things like that. You can also affect, you know, your neutrophils too, since they are phagocytes, even though it doesn't really show that on this chart here. Defects and phagocytic cells are significant because it affects two major functions, your ability to kill microbes, like the phagocytes fail to destroy ingested microbes, and some examples of this are chronic granulomatous disease, also known as Cgd, and affects interactions with others. And then you have, oh, that got scattered. scattered. Sorry, you guys. So, this is supposed to say number two. Where's my mouse? Interactions with other cell types is supposed to say number two. So, where's the mouse? where's the mouse? Oh no, okay. So, this is number one, and the example is chronic granulomatous disease, and I made a mistake here. This is supposed to be number two over here, and the example is G6PD deficiency, and hopefully you guys have heard of that before. If not, you'll hear of it, I believe, in MPP at some point. And so, when we go through these guys here, I cross out this third one because, you know, there are other diseases here that you could talk through, but I don't want you to know myeloporosity sufficiency, so I drew a line. And the only reason I did the box around is because it leads to defective respiratory bursts, and phagocytes are unable to kill pathogens here. So, we have a C6D deficiency here. It affects, it has a defective gene or protein at the nicotinamide adenine dinucleotide phosphate, or NIDPH oxidase. So, as you guys know, you know, phagocytes are very important for that reactive oxygen species production, stuff like that. And so, you know, by affecting that, you have defective respiratory bursts, and phagocytes are unable to kill the pathogens here, which can lead to chronic bacterial and fungal infections, granulomas. We talked about C6D, oh my gosh, C, G, D, there we go, C, G, D, overall here. Then we talk about G6PD. This is glucose 6-phosphate dehydrogenase deficiency. It's one of my favorite immunodeficiencies. It's just, it's so cool to me, and it's one of the first ones I ever learned about when I was like, oh, I kind of like immunology, like I want to learn more about this. But also, like C, G, D, it is defective respiratory bursts, and the phagocytes are unable to kill pathogens. So you will also see chronic bacterial and fungal infections, and some will actually induce anemia overall here too. And so again, I did put up the reminder, no C, G, D, and G6PD, but I didn't box them without their clinical effects of accidentally boxing this one down here too. So this is one of my favorite books overall. It's called Survival of the Sick, and it just proposed the hypothesis that modern disorders that we see may have evolved as evolutionarily like protective mechanisms in the past. Like one person has proposed that diabetes, while a debilitating disorder now, may have actually given our ancestors an advantage because if you have increased solute in your blood, you have a lower freezing temperature, and so you're more likely to survive an ice age. And so some people propose that, you know, diabetes may have developed, and patients who had it, you know, survived the ice age, and therefore were able to pass those genes on. So just a really, you know, cool book to read, just a kind of, you know, hypothesis, you know, like why we need it all overall. And so G6PD deficiency is hypothesized to have been an evolutionary response to malaria, because they did find that children with the African variant of the G6PD had twice the resistance of Plasmodium falciparum, one of the causes of malaria, and the most severe type of malaria than children without it. And so the premise behind it is that does it provide us an advantage where, you know, it's die now versus die later. Like, yes, these are debilitating diseases, but they gave us a slight advantage. So we do have a quick video on it just because I love this. So it's one of my favorite disorders because, like, that is super cool to think about overall. But again, the hypothesis die now versus die later, and especially with the fact that it does provide some protection against malaria. And I do know several individuals who do have this disorder and they are of, like, Italian and Mediterranean descent overall, too, where you have, you know, higher rates of malaria originally. Group 6 is defects in intrinsic and innate immunity. And again, here are the different types of defects to innate immunity. Obviously, it will affect your response to various pathogens here. And so you have predominant susceptibility to invasive infections with pyrogenic, so it causes fever, bacteria. You have predominant susceptibility to viral infections, so like herpes simplex encephalitis might be more at risk with certain individuals here. You also have more at risk for parasitic infections and fungal diseases and some that are more susceptible to mycobacteria, like mycobacteria tuberculosis infections here, too, which is fascinating overall. And so that's all I want you guys to know from this one, is it affects intrinsic and innate immunity, leading to susceptibility to pathogens that could make you sick, and it is, you know, separated by, like, bacteria, viral infection, fungal diseases, and mycobacteria overall here, too. Now, autoinflammatory disorders, you know, it does kind of sound like autoimmune, and it is loosely related here, too. A lot of people link immunodeficiencies with autoimmune, but autoinflammatory disorders, like it sounds, the body, you know, self-inflams basically here. And so you can see some with recurrent inflammation, you have some with systemic inflammation with a rash, and you have some that has sterile inflammation, which means it's occurring in areas where you do not expect to frequently see infections, so, like, within the bone or the joints or, like, deep within the skin, where the bacteria should not be. And so that is pretty cool when you can kind of organize it by that way here, too. And then they have a grouping for others, because they're still trying to figure out how we want to organize these guys here. You also have complement deficiencies as group 8, and complement defects can impair antibody-mediated immunity and cause immune complex disease, especially if you affect the ability to remove complement from the body here. And so we do classify them whether you are a higher susceptibility to infection or a lower susceptibility to infection, and presentations from that. SLE is systemic lupus, and it's basically systemic lupus-like syndrome here. There are some people who are more susceptible to pyrogenic bacterial infections or nesirial gonorrhoea or meningititis infection here, which is fascinating. So we can even sort by, like, what specific bacteria they are more susceptible to infections, which is wild. And notice, again, some of these terms are things you've already seen, like, you know, C9, C5, you know, there's a deficiency in C7. Factor H is involved in one of the different pathways for complement pathway, things like inhibiting C1 or CD59. So there are a lot of different opportunities, you know, for complement deficiencies overall here. And again, if you take out complement here, you know, you take out the ability to have the optionization since, you know, those complement proteins like C3b work as oxidins. You know, you have a failure to induce certain types of inflammation from there. You know, you can take out the manin binding lectin pathway, you know, that's completely affecting that one. Or, you know, if again, you know, you've got, you know, aspects and defects in classical complement pathway, then obviously you can trigger that one out or even the alternative. So it can affect one or all three. It depends on kind of what you're taking out overall here. And there are numerous student defects involved that increase your susceptibility to infection and sometimes to risk of autoimmune disorders as a consequence here. And so if you have defects in the alternative pathway or manos binding pathways, so MBL, and components, you'll have increased susceptibility to bacterial infections because if you think about what that pathway does, it's more important in activating in bacterial infections here. However, if you have defects in just the classical complement pathway with the exception of C3, which you guys know is important for all of them, if you just have a defect in classical pathway except for C3, these guys are not associated with an increased susceptibility to infection because you're just kind of taking out, you know, the classical complement and manos binding lectin and alternative actually step up and kind of protect the body from this. And so, you know, they do work very well together and so if you kind of take out one of them, it can still, like, you're still protected. It's like the backup plans from the body here. With the exception, obviously, if you affect C3 in any way, that will take out all three of them because, again, they all use that C3 convertase overall. However, with the classical complement pathway, there is an exception. You are more susceptible to encapsulated bacteria that can usually be targeted and attacked by antibodies and so this is an important feature to know overall. And obviously, I've mentioned here, too, because, you know, if you do take out the classical complement pathway with these exceptions, you know, the MBL and alternative pathways do generate sufficient complement mediated protection, thus, you know, protecting the body even though you've knocked out complement. So, there are a couple different subtypes and, you know, varying severities overall. Obviously, C3 deficiency would be one of the worst because all three of them to use C3 and so they have severe problems with recurrent infection and with immune complex mediated disease because of the key role C3 plays in all three complement pathways here, too. If you have deficiencies in C1, 2, or 4, if you guys remember, that's, you know, the classical complement pathway and so you guys just kind of take that one out and so you'll have inefficient clearance of immune complexes. We do know you have increased risk of type 3 hypersensitivity diseases, which we'll talk about a lot more when we do hypersensitivity lecture here. We do see more injury to kidneys, joints, skin, and blood vessels as a complement, like an effect of this. There's also one where we can actually affect CD59 and if you guys remember CD59, CD59 kind of blocks membrane attack complex from forming unhealthy cells and so, obviously, if you block this helper here, it will allow the accumulation of complement complexes, including MAC, on host cell membranes, thus leading to cell injury and death in healthy cells that should not have been affected. And so, again, a couple different varieties here. There are other factors involved here, too. We do know if you take out C5 through 9 for whatever reason, you're more susceptible to Neisseria, but the ones I really talked about here are these guys here. So you want to enforce E3 and then that CD59 deficiency here. So that is the end of that one and let's jump into the second two-meter deficiency here. And so, obviously, this is the asynchronous recording for today because the research days is today. So this is Nikki's dog, Eugene. He's a six-year-old Pomeranian. More pictures of Eugene just being a handsome prince overall. You guys do have a drop to note due Monday. It is blood groups ABO and that RH factor. Well, this is where we're at today, even though, obviously, we're spilling over. And I do have that on purpose. Like, I do know transplantation and, you know, this lecture, transplantation, cancer, kind of all spill over. And so, like, next week is just kind of vague just to make sure we get caught up on everything before the asynchronous hypersensitivity recording, which I will post on 11-25. That is from former student Dr. Pham, who was a BMS student and then went through our med school here and he is now a first-year resident. Actually, no, might be a second-year resident now at University of Cincinnati as an anesthesiologist, which is super awesome here. And so, we'll first start out by talking about immune evasion just because, you know, some people still get sick. And just because you get sick does not mean that you have an immunodeficiency disorder. It can just be that pathogens are just very, very good at subverting your immune system because, again, they want to survive, too, just as much as we do. And so, they develop ways to subvert our immune system. So, just because you get an infection doesn't mean you have an autoimmune disorder or an immunodeficiency disorder. And so, there is a difference between, like, HIV, which is one of our classic secondary immunodeficiency disorders, and just having infections in general. And so, I do want to clarify that before we move on. So, there are going to be some examples of just how, you know, bacteria, viruses, and things like that subvert our immune system. And so, some pathogens use genetic variation to help us prevent effective long-term immunity overall. So, one example that we have is that strep pneumoniae, which causes strep throat. It has many different serotypes, or sub-examples, and that's what's shown here by all the different little, you know, colored shapes on the surface here. And so, you know, serotypes are different strains of S. pneumoniae here. I'm sorry, this causes not strep-iogenes causes strep throat. S. pneumoniae causes, in fact, pneumoniae. Sorry, you guys. It's not critical to this discussion, but strep pneumoniae causes pneumonia. Strep-iogenes causes strep throat. And so, there are many different serotypes of S. pneumoniae, and they all have antigenically different, so these are all the different antigens on the surface, but they're all different capsular polysaccharides on their surface here. And so, they all differ in terms of the shape. Like, yeah, these are both, you know, rectangles, but this one's orange, and this one's pale blue. These are triangles, but this one's green, and this one's like blue or purple or whatever. And so, a person can become infected with one serotype of strep pneumoniae. You know, you go through normal immune response, we make antibodies, we clear the infection, voila, antibodies bind on. However, these are, you know, antibodies are made for these yellow triangles here. So, if you get infected with a different serotype, like the blue circles here, these antibodies won't recognize this new serotype of S. pneumoniae. And so, as a consequence of it, you have to make a new immune response to it in order to clear this infection, because there are a lot of different, you know, capsular polysaccharides. You can get infected with strep pneumoniae many different times, and it's not just saying that your immune system is not, you're not immunodeficient, your immune system is not doing its job. There are just a lot of different serotypes that come are here to subvert your immune system overall. And so, again, just because you keep getting strep pneumoniae does not mean you have an autoimmune, or immunodeficiency, it does mean that, you know, strep kind of sucks. It's a very, very effective pathogen. Another example is that you have mutation or a combination allow the influenza virus to escape from immunity. So, we use that example last class too, like prior classes where, like, they can, you know, shift their different antigens on the surface, and so, like, your body doesn't recognize them overall, and they change enough that, you know, Nathan could cough on his neighbor, but still get infected with the strea, because by the time it reaches Sabrina, it's mutated enough, but it doesn't look like the virus that he's already encountered here too. So, there are two main terms we use with influenza specifically. We have something known as antigenic drift and antigenic shift. I always like to keep them straight in my head by thinking of drift as, like, a very peaceful little tiny wave, like, you know, you're, you're drifting in a wading pool, like, it's not, it's peaceful, it's slow, nothing crazy. When you think of a shift, I think of, like, an earthquake and a gigantic change in something, or, like, a shift in the tectonic plate, it's, like, a big deal. So, antigenic drift is minor small point mutations overall that just slowly and gradually cause alterations to the structure of viral surface antigens. This is what causes our year-to-year antigenic differences in strains in influenza and why we need, you know, that annual vaccine, because, again, that, you know, every single time a new person gets infected, there are those tiny point mutations, they just drift along, and they just, you know, change. So, by the time you, you know, see the same potential virus again that's just been circulating around your class, you don't have antibodies that recognize it anymore, just because, you know, again, it's drifted with each new infection, versus a shift. A shift is a major jump, and that's what we're seeing right now with H5N1, where it was jumping from cows and pigs to now humans. And what happens is this, we'll talk about this a lot more in micro, but this is specifically when influenza viruses completely reassort their segmented genomes, and this is why they're able to, like, you know, take pieces of cow influenza or sheep influenza or pig influenza or whatever and mix it together because it has segmented genomes. So, its genome is not one linear line, it's pieces of it. And so, as a consequence, if you have an animal, and it's usually like, you know, pigs, etc., get infected with both human influenza and, like, a cow or, you know, any other animal, you can have this change where those segmented genomes will swap, thus giving you radically different surface antigens than things we haven't seen before. Like, if you've never been infected with a pig influenza because we're not pigs, you're not gonna have antibodies to these new, you know, pig antigens. And so, this gives us rise to new viruses, which is caused by this antigenic shift, and they're the usual cause of our influenza pandemic. So, what we're seeing right now with H5N1 is a perfect example of an antigenic shift. Or bird fluid, I went through, or swine fluid in 2009. That was another big example of that one, too. And so, this is showing you the evolution by antigenic drift up here. And so, again, antibody will bind on to hemagglutin, a protein found with viruses here. And this will actually prevent the virus, we're gonna call it virus V, from infecting this person P here. We're gonna say Nathan. I'm just kidding. And so, antibodies de-bind on, neutralize, and prevent it from binding on here. But then, this virus goes on and infects person Q, and this virus originally mutates to give us this, you know, virus kind of a tiny point mutation here. It has this altered hemagglutin. And so, person P doesn't have antibodies that recognize this anymore. And so, when this new virus comes back and, you know, is exposed to person P, person P has no neutralizing antibodies against this new, you know, minorly changed virus V. And so, as a consequence of this, this person can now be infected because those antibodies are basically, you know, pointless at this point here. We get H, or not HIV, influenza names, like when we talk about H5N1. Those come from the terms hemagglutin and the neuraminidase, obviously. Hemagglutin is the H, neuraminidase is the N. There are a lot of different varieties. That's why we have, like, H1N2, because that's the second neuraminidase, and the first hemagglutin, or H5N1, is the fifth hemagglutin we've identified, the first neuraminidase. And so, there's being, there's various mixtures and things like that, that will create overall. But again, these are showing those tiny little point mutations that just, you know, change it just a little bit here, to the point that person P, who had antibodies against the original virus, is no longer protected just because of this tiny point mutation change. Versus when we talk about an antigenic shift. This is when, I mean, you frequently use pigs because pigs, unfortunately, are common vectors of these guys here, but they can be infected by a lot of different types of influenza. And so, this one pig cell, or one pig, became infected with both a human influenza and a bird flu. And since they have segmented genomes and pieces of it, what it's showing here is this reassorbent, where, you know, this new virus gets a recombination of a piece of an avian influenza and some human virus that creates this whole new variety of human gluten in this specific example. And no humans have antibodies to this because, again, it came from birds. We hadn't seen it before. But again, it took a just enough mutation, where it picked up some humans and some birds here, that it caused a massive shift. And so, none of us, you know, have protection against this. And so, our entire population will then become vulnerable to infection. That's why it's been so critical with HIVN1 to isolate in quarantine, especially when they found out animals have it. And we do frequent animal testing, especially if you live on a farm, to make sure there are no new viruses popping up, because then they're just, they'll just kill all the animals to kind of prevent it from spreading, because that's one of our best, you know, our best, our best defense is a good offense. So, we will do that instead. But unfortunately, we do see humans spread now with this current HIVN1, but we are still trying to keep it limited and quarantine people as soon as we find it. So, another thing we'll talk about are trypanosomes. And they are, you know, eukaryotic pathogens here, and they use gene conversions in order to change their surface antigens overall here. So, don't panic by this picture. It's just kind of showing you some genetics. Don't stress. It's showing you antigenic variation by African trypanosomes, allows them to escape from adaptive immunity overall. We'll talk about this a lot in micro, because they are pretty cool. They cause African sleeping sickness. But they have many inactive genes. So, say this is a variable surface gene on the surface. And so, you know, genes for their various surface antigen here. But they only have one site for expression. And so, they only have one variable surface antigen presented on their surfaces at a time. And so, once you have antibodies made to that specific antigen, it can actually go through and alter which gene is expressed, which would then give you a new surface antigen expressed on the surface here. And this one's showing you this, you know, B. This started out as A. And so, you know, we get infected. The body makes antibodies to A, starts controlling the infection. The parasite realizes that, moves on, expresses this second B on the surface here, which is different from the first. Our body has no antibodies to it. So, we have a flare of an infection. It activates the immune response. The body starts making antibodies to it. And then, I lost my mouse. But we would move on. And same thing. The parasite would start expressing C, because again, it's trying to subvert our immune system and expresses a new surface antigen. So, look, there's over a thousand different ones that it could use overall. And so, with patients who have this infection, we're going to see peaks of disease, because we're showing here, we're showing here that these are the disease that were being presented here in the red. So, that's the red box here. But then, notice this dashed line is showing antibodies that we created for it. And so, again, we see trypanism infection decrease, because again, we have antibodies that are controlling it. However, during this process, it realizes, you know, the body is making antibodies to it. It goes through and changes that variable surface antigen. And so, again, we have no antibodies to this. And so, we get a brief peak in infection again. If your body makes antibodies to this new variable surface antigen, controlling it. And then, it'll do the same thing again. It swaps it and makes the blue one. And so, again, you have a brief period of disease before the body catches up and makes antibodies to that one. And it'll just continue on and on and on and on and on. So, we frequently see recurrent infections with the same parasite in African trypanosomiasis, just because of this variable surface antigen that it has. It doesn't mean that a patient is immunodeficient. It just means these parasites are very, very good. Another example to talk about is herpes virus. Herpes viruses persist and we have chronic infections to it, not due to immunodeficiency, but because these viruses go latent and hide from the immune response. And so, one example here is that with an initial herpes infection, you do have, you know, the breakout along the mouth, but you will have clearance by an immune response. And so, that causes the virus to travel up the trigeminal ganglia and hide out, actually, in the brain here. And again, you have immune control of it. However, in times of stress, in times of stress, so even menstruation, sunlight, exams, things like that can trigger, you know, it suppresses the immune system a little bit and trigger reactivation of the virus, where the virus travels back down to it and starts infection all over again because it travels back down the trigeminal ganglia and causes infection on the surface. Your body amounts a successful immune response, clears the cold source. Again, the virus travels back up and remains latent. And so, it's just back and forth and back and forth and back and forth. Doesn't mean you are immunocompromised. It just means the virus is really good at hiding and subverting your immune response. There's other things that they can do, like they can directly attack our immune system, too. Like we can subvert immunoglobulin A by bacterial immunoglobulin A binding proteins. So, they can actually, you know, attack IgA and mucosal membranes. That makes you very, very good at causing infection, like your sinuses and things like that. And so, as you guys kind of remember from the last module, you know, IgA can recognize bacteria. In this case, it binds on and you have those FC receptors. And again, look, it's alpha for the IgA. Binds on recognizes that FC region tail, you know, pulls it in and, you know, phagocytizes it, destroys it, host wins. Bravo, great job here. But we have certain proteins, like SLLP7 is one example here, that will actually bind on to complement C5 and that FC region of an antibody. And if you see it here, it's blocking that tail. Because the tail is here, that FC alpha receptor does not, you know, see it. It's been blocked. And also, too, it's presenting a C5 on a surface. So, it looks like it's hiding out in between. It looks like host. The body won't recognize it. And this is able to subvert the immune system and kind of, you know, beat your immune system overall. And so, in this case, the pathogen would win because it's kind of, you know, hiding out and protecting your body and subverting its normal immune response here. This is what's known as a superantigen, though, SLLP7 specifically. And so, it is an example of a superantigen. It's not elaborated in this picture here. But just by definition, I want you guys to know this just because we will talk about this a little bit more with microbiology. But a superantigen is a molecule that, by binding non-specifically to MAC class II molecules and T cell receptors, will actually stimulate polyclonal activity of T cells. So, we just showed one example with SLLP7. But something else that it can do, too, is it can actually trigger T cells to divide and activate them without them, thus kind of leading to, like, autoimmune disorders because the body is so, like, it's activated. There's lots of division. It's trying to fight something. It doesn't know what's going on. So, it's basically like a distraction. It's telling the body to attack itself and look at the other things. Meanwhile, the bacteria subverts and survives. So, there's a lot of, you know, nifty ways that bacteria are constantly trying to fight back and not keep us safe overall. And so, obviously, if we have a failure of the immune system, we have a reduced ability to resist infection. And so, you know, that's why you can see these diseases here. It doesn't always mean it's an immunodeficiency disorder, but immunodeficiency disorders are specifically where we've taken out an aspect of the immune system, usually genetically, especially when we talk about primary immunodeficiency disorders. But we will talk about secondary today because these are caused by the environment, or we've damaged the immune system later. And some of them are viral, so certain infections can lead to immunodeficiency. We'll talk about HIV a lot today because HIV is one of those few examples, because it really actually destroys the immune system. It depletes your CD4 T cell count. And obviously, if you take out T cells, you can't mount successful adaptive immune responses overall. You've taken out the general of the army. Other therapeutic treatments, like certain drugs, even cancer and chemotherapy, can deplete the immune system too, because like radiation can destroy immune cells, you can damage the bone marrow, stuff like that. And malnutrition, if you don't have the proper nutrients, can lead to the development of immunodeficiencies, because again, you don't have the nutrients needed for the cells to function basically in the normal. With these guys, they occur at any time in life, depending on when the exposure of the causative factor occurs. But it is important to remember both primary and secondary are characterized by our current or chronic infections, obviously excluding herpes and stuff like that. Some can make you more susceptible, but again, herpes is just nasty on its own. The variable surface antigens of trypanosomiasis, it doesn't mean you have an immunodeficiency. It's just those are very good parasites and pathogens overall. But you will have also an inability to clear infectious agents after standard antibiotic therapy too, which is important because again, antibiotics should help kill off bacteria. And if you're still with a antibiotic bacteria susceptible to and your immune system, you should be able to clear it. And if you don't, something's wrong. Or if you get infected by really weird pathogens that are usually not seen in humans, something else is probably up. This is just a really pretty picture overall. I actually forgot what this picture was. Oh, it's HIV virus. It's blue, the blue dots being shed from an infected T cell. Because again, HIV is an example of a secondary immunodeficiency disorder because it takes out and destroys your T cells, uses them to make new baby viruses and viral factories. Unfortunately, thus spreading the virus and when you take out the CE4 T cell in general, you have immunodeficiencies overall. So it does arise from environmental exposures that may occur at any time in life, depending on when an exposure occurs. So when we talk about secondary immune deficiency, HIV is one of them. Environmental factors, like we mentioned before, could be physiological sequelae, like malnutrition. If you don't have the nutrients you need, therapeutic treatment like chemotherapy can affect, or certain drugs can affect your immune system here. Obviously having cancer, if you have malignant lymphocytes or monocytes like lymphomas and leukemias, it can crowd out normal hematopoietic cells like we talked about, kind of like you have a limited amount of volume. And if it's taken out by a million different lymphocytes that the cancers are not really functioning well, you could lose your monocytes and therefore have decreases in macrophages too, or lower levels of neutrophils, things like that. Or infection, which is HIV here. The status from 2019, they really haven't updated too much of it then, but even back then there were over 38 million people living with HIV. The number is definitely for sure gone up. Newly infected, we had roughly 1.7 million new people infected, and with death we had roughly 700,000 deaths overall. I don't know why it says million there, because it's not million. But it does increase and there's breakdown of children, men, women, and adults overall. Now we look at HIV virus. We'll learn a lot of these guys more so next semester here, but this is what it looks like when they're getting electromicrograph that's been colored. You have spike proteins on the surface, so not just COVID. Lots of viruses have spike proteins on the surface here, but it is a retrovirus, which is really cool because it is an RNA virus. And as you guys know, central dogma of molecular biology is DNA to RNA to protein. We call it retro because it's going backwards. Again, if you're showing close from the 80s, it's retro now apparently. But it's backwards because it does go against that central dogma of molecular biology because it uses reverse transcriptase to actually take its RNA virus, convert it into DNA, and actually insert itself into your genome so you have it for the rest of your life. And so it breaks that central dogma of molecular biology, which is why we call it a retrovirus here. HIV can infect CD4 T cells, monocytes or macrophages, and even dendritic cells. So it can affect a lot of different aspects of the immune system, both the innate and adaptive overall. And we will stop here just because I think I'm over time on the recording here. Obviously there are a lot of different proteins involved before you guys panic. I would know just these these three that I bolded here and then these two here because they're actually different subtypes of the virus, mainly HIV1 and we differentiate them by the presentation of VPU and VPX. So I would know because it's bolded, VPU, VPX, gag, pull, and envelope. VPU, VPX, gag, pull, and envelope. And so they are described here. There's a lot more than just that, but I would know those for sure. And we will stop there for today.