In this lecture we look at pathologies that interfere with immune function. In our lectures on pathogens, we looked at ways that the pathogens thwarted, damaged, or they did our attempts to attack and get rid of them. This lecture looks at a different set of problems. Immune deficiencies are caused by genetic mutations and the production of non-functioning proteins. In other parts of this series, we look at the unfolding development of all those marvelous cells that cooperate to protect you. As a hematopoietic stem cell begins to generate, it makes a series of decisions, committing it to one or more specifically pathways to the differentiation of a specific cell type. However, Murphy's law applies to biological systems as well as engineering, and anything that can go wrong, will. All of these branch points require signals receptors for those signals, and further changes to the regulation of gene expression. Every aspect of this process uses one or more proteins, and each and everyone of these proteins is coded for in the chromatin. Here is a diagram of the 22 human autosomes, and the X and Y sex chromosomes. The stripes are the result of staining, which is dark in the region of the chromosomes that are unexpressed or not used to make RNA. Genes important to our immune function are scattered throughout the genome. At one point I thought there could not possibly be a gene on the Y chromosome important in the immune response because women would lack it. Luckily, I Googled Y chromosome immune function before writing this lecture, low. There is a repeating element on the Y chromosome that's linked to susceptibility to autoimmune disease. Which raises another important point. Mutations don't have to be in the coding region of a gene to affect its function. Regions that determine gene expression, and availability are also important and can also go very wrong. But it is faulty jeans on the X chromosome that you're more likely to hear about. This is because females have two copies of the X chromosome, and boys have only one. Most, but not all, mutated genes function as Mendelian recessives. As long as you have one good copy making some protein, you show little or no evidence of the disease. But males have only one X chromosome, and if it doesn't have a good copy for some gene, you will see the effects of not having that protein. This is basically a list of all the genes on the X chromosome. It's a compendium of the awful things that can happen to your boy babies. And many of these problems arise from not having some protein necessary for immune function. This explains why many immune deficiencies are problems experienced almost exclusively by males. But there are also defective genes in the autosomes, and in fact many more of them. But most of them are recessive, so you have to be really unlucky to get too bad copies and the resulting deficiency. But it can happen. So let's start at the beginning, with the hematopoietic stem cell and study a few examples that illustrate the fundamental principles. Here is a representation of the source of it all, our cartoon of the hematopoietic stem cell. One of my Indian pre-meds asked me to use Ganesha, his favorite god, to represent one of our cell types. After a brief consideration, we agree that Ganesha embodied many of the trace of a hematopoetic stem cell. Ganesha is the god of new beginnings. He overcomes obstacles, and will support you in overcoming yours. He is powerful, and possesses complex wisdom. What better way to represent a cell that is the source of all immune cells, the foundation of defense against overcoming pathogens. And is so powerful that just 100 cells have the knowledge and capacity to regenerate the entire synthetic capacity of our bone marrow. Our figure here wears a crown, representing the variety of cell types the HSEs can give rise to. Our HSE rides a bone marrow stromal cell carriage indicating interactions with the cells that moved. For Intiation forward and the carriages drawn by a lab rat. A nod to the tradition that Kanesha uses rodents for travel and protects farmers from the pestilential depredation of rodents. Rats and mice are also very important experimental models. Advancing our knowledge of immune function. Our HSE figure holds a TLR 4 receptor in its trunk. This is the toll like receptor that responds to LPS a powerful initiator of the immune response. We call that we use modulated versions as immune agents. Activation of TLR 4 jump starts hematopoiesis, that is, it will prompt both cell division and cell differentiation. Necessary to produce the range of cell types we need to fight off the infection. Now, ordinarily, HSE is a relatively coiesent. However, if a person must fight off an infection, the agencies will begin to divide and provide a source of differentiated cells. In the necklace you can see the nuclear factors that are then activated to help expand the number of HSC's. There is bmI I transcription factor in the polycomb family. It's called RING finger protein 51. This prompts HSE cell division and keeps the population of cells undifferentiated and continuing to divide and replenish itself. There is ARID3A, the 80 rich interactive domain containing protein 38. This is a transcription factor that regulates the cell cycle, an linneage differentiation. An also promotes expansion of the population of cells. The third jewel dangling from the necklaces miR-146 A. Now this is not well understood, it's part of a family of conserved micro Rnas that govern gene expression. This particular version is associated with responses involving NF-kB. The forearms of Argon Asia indicate power to perform many functions at once. Here we are using them to hold out surface proteins. That is, those proteins embedded in the membrane and extending outward from the cell. First we have CXCR4 which is a 7 span chemokine receptor, that will receive signals an activate internal signaling cascades via a G protein. We also have CD117, the C-klt receptor. This is an immunoglobulin receptor for stem cell factor, which maintains the undifferentiated state in HS series of germ cells. Also we have CD 34, CD 34 is a single pass glycoprotein with cyalume you things on it. That is is one of our acidic proteins that interacts with stromal cells. It's part of the cell adhesion system and it is one of the factors that is used in the process of identifying and isolating them. Our 4th protein is CD 44v1-6, a cell surface glycoprotein. It interacts with stromal cells controls migration. And HCS can migrate in and out of the bone marrow, an important trait that allows doctors to transplant HCS by simply adding them into an RV. And this seems to be one of the signals that allows them to home in an go back to the bone marrow. RHSC's rings represent two versions of an interesting group of membrane proteins, the GPI proteins. The GPI proteins are tethered to the cell membrane, but not embedded into it. They are attached to phosphatidyllnoistol. You can see the lipids part here, which is embedded in the outer leaflet of the cell membrane in, in particular, in the lipid rafts. The inositol is also then attached to a string of six sugars. And that actually makes this portion so far egg like a seal of phosphatidyllnoistol. The terminal sugars of this group have ethanolamine added to them and that is important. Because what's going to happen is this membrane imbedded structure will be attached to a protein after the protein is made. That is post translationally by its carboxy terminal. So what happened here is this protein is then tethered to the plasma membrane. Protein on the outside in something embedded in a nice widget lipid raft. Note that clipping any of these glycosidic bonds between the sugars will release this protein, like a helium balloon let go by a careless child. And this means that the cell will attach to whatever this protein binds to until the glycosidic chain is clipped and the protein is let go. We see the two examples here. Stem cells antigen one SCA1, which is relatively specific to stem cells, implying interactions with the stromal cells of the bomb barrel. We also see THY1, which is thymicide differentiation, antigen one also called CD90. This GPI protein is also found on sinuses as they leave the bone marrow an enter the sinus. After entry, the protein declines, suggesting that it is functioning to target the T cells to the thymus to complete their differentiation. Well, this is the source. We start from here and then go through a variety of signaling processes that will specify the functions of individual cells in an increasingly narrow way. And that's who we see here with a pluripotential progenitor cell giving rise to all of the various cell types that are produced in the bone marrow and in the thymus. So here is our pluripotent progenitor cell, one that is CD34+ and is basically another way of referring to hematopoietic stem cell. When we first looked at hematopoeitic stem cells in the first unit of this lecture series, we refer to them as Lynn minus. That is, these were the only cells that didn't have specific surface markers on them related to either the myeloid or the lymphoid lineages or their various branches. Now that did not mean the cells didn't have any interesting surface proteins, or that they were some senses blank, as we have seen. Because they must regenerate themselves and keep the population supported as they lose cells into various differentiation pathways. So maintaining a population of HSCs is a complex process, and requires a multiplicity of different signals. It is not surprising the defects in this process are rare, because if you can't maintain your HCSs, you will wind up with neither adaptive nor innate cells, and you're going to quickly succumb to infection. Rather surprisingly, however, mutations that affect the reproduction of HSCs and the differentiation of precursors to the two main branch pathways, do not usually come from mutations in the protein signals we just discussed. Most of those signals are so fundamentally important in controlling cell division and differentiation generally, that anything with a non functional version just is not compatible with life period. Embryos with those kinds of mutations don't survive any length of time at all. The mutations that blocks the foundations of hematopoiesis are often those that compromise energy or raw materials production. So we're going to look at basically just one example of this, it's verticular dysgenesis. And its stems from a mutation in one of the genes called AK2, that equilibrates phosphates among ATP, ADP, and AMP. Do you know anything about that process? You will think that if you can't do that, you can't even make it as far as an eight cell but it turns out that AK2 is one of three different versions. You have three different genes for this particular function, and so if you're mutated AK2, you can't use one of them. And this compromises energy production without eliminating it. It's just that bone marrow cells are about the fastest dividing cells in the body, and are very sensitive to insufficient energy. So when this case, what will happen is the stem cells will undergo apoptosis, neither replenishing nor producing hematopoietic precursors. And that produces a dead end for both adaptive and innate immunity. Children born with this die of infections within days, although there are treatments including bone marrow transplants. Reticular dysgenesis is one of the examples of immune deficiency diseases referred to as SCIDs, that is severe combined immune deficiency diseases. Clearly, if you can make neither meyloid nor lymphoid cells, you will have it combined deficiency. However, the ability We need to make just E cells can produce a similar result, because T cells are the coordinating force that drives both the adaptive and innate responses. So let's look at lymphocyte defects next.
