Usmle Animated Immunology - Phagocytosis & chronic granulomatous disease

Hi guys so lets pick up right where we left off in the last video, where we examined how the innate immune cells recognize foreign antigen & then the subsequent secretion of chemokines by macrophages once they've detected an intruder So now lets add another layer to the picture, & begin exploring what happens once the phagocyte detects a microbe or a cell that is expressing a foreign antigen, & how it comes to deal with terminating that foreign invader in the process of phagocytosis which in itself is really quite fascinating when u remember how diverse and adapted all the cells in our body really are especially when u consider that there are billions & billions of cells in our body all workin together in harmony Now the steps of phagocytosis are particularly important to know, because as we'll see later on, defects in the process of intracellular killing post-phagocytosis can leave hosts particularly susceptible to severe & persistent infections as in the case of chronic granulomatous disease So we have our phagocytic cell,for example in this case, the macrophage, which is standing guard, assisting our innate immune defenses by using its pathogen recognition receptors it detects the foreign antigen of microbes, in this case a bacterial cell what happens next? well a number of things 1. as we saw in the previous video, the macrophage becomes activated & begins to secretes chemokines and acute phase proteins, such as your interleukins and tumor necrosis factor which not only activate the rest of our immune cells, both innate & adaptive immmune cells, they also have effects on the body as a whole, for example effecting the endothelium as well as causing fever, and therefore generally making the bodys environement more hostile to invaders So Next, lets see how our phagocyte phagocytoses the bacteria & then digests it with enzymes intracelluarly... the first step in phagocytosis... is the extension of pseudopodia from the phagocyte to wrap around & engulf the bacteria then the pseudopodia fuse together to trap the bacteria inside the phagocyte in whats called a phagosome now in this case our macrophage, which remember has lots of digestive ezymes contained within lysosomes, as do our other phagocytes, now these lysosomes fuse with the trapped bacteria in the phagosome, to form a phagolysosome & this exposes the bacteria to the enzymes contained within & subsequently kills the bacteria Now this intracellular killing within macrophages happens by two different methods, the first method is by Oxygen-independant killing, and this form of killing, as the name states, doesnt require oxygen & is performed by enzymes such as lysozyme - which digests bacterial cell walls by cleaving peptidoglycan, defensins which form pores through bacterial cell membranes, & then you have things like lactoferrin which chelate iron & also some other hydrolytic enzymes ... but the main thing to remember here with these enzymes is that their methods of killing are carried out without oxygen, and these are grouped collectively as oxygen-independant killing mechanisms, lysozyme, lactoferrin, defensins and hydrolytic enzymes the other mechanism of intracellular killing does requires oxygen, and is thus oxygen -dependent and you may have heard this being referred to as the respirartory burst, as its only know now this category of oxygen dependant killing further divides into 2 different killing methods, with both being centred around the generation of oxygen-free-radicals the first of our oxygen-dependant killing mechanisms is by an ezyme, NADPH oxidase which reduces oxygen to superoxide anion, which then generates hydroxl radicals & hydrogen peroxide which are both toxic & deadly to microbes, so it basically generates lots of oxygen free radicals the second oxygen dependant method is by another enzyme, myeloperoxidase, which combines chloride ions with some of the hydrogen peroxide formed by NADPH oxidase to produce hypocholrite, which interestingly enough is actually the same active ingredient that you'll find in a bottle of household bleach under your sink So those are your various intracellular killing methods that happen after phagocytosis, and the main thing really to remember is that they divide into oxygen-dependant & oxygen-independant killing mechanisms & the more important one is actually the one that requires oxygen - the oxygen dependant killing method, the respiratory burst, which is quick and effectove And therefore defects in the oxygen-dependant killing within phagocytes actually has an important clinical correlation & that is in the development of chronic granulamatous disease, where patients suffer from chronic severe and persistent bacterial and fungal infections, specifically from catalase positive organisms and this is actually due to an inherited deficiency or defect of NADPH oxidase - so the phagocyte struggles to produce the oxygen free radicals which are needed to destroy the catalase positive organisms now why is it only catalase positive organisms and not catalase negative? Well the function of catalase is to break down hydrogen peroxide into water and oxygen, preventing it from used by myeloperoxidase to form hypocholorites ions to destroy any would be microbes So far, we've examined anitgen detection & phaocytosis, but theres another key feature to examine... anitgen presentation, and thats what we'll be having a look at in the next video