Chapter 11 -- Last blog post?!

1. Chapter 11 discsses autoimmune diseases, which come in three forms analogous to hypersensitivity types II, III, and IV (Ab's made against self cell surface or extracellular matrix, soluble immune complexes deposited in self tissues and reacted against, and effector T cell self-reactivity).  The first section of the chapter summarizes the effects of these autoimmune types and then illustrates them with an overview of several particular autoimmune diseases: autoimmune hemolytic anemia, Goodpasture's syndrome, Grave's disease, Hashimoto's disease, Type-I Diabetes, Systemic Lupus etythematosus, rheumatoid arthiritis, multiple sclerosis, and myasthenia gravis--the section also distinguishes between agonists, which are autoantibodies that facilitate receptor function, and antagonists which inhibit receptor function.  The second portion of the chapter discusses the origins of autoimmune diseases, citing mainly non self-tolerant T-cells due to failed negative selection in the thymus, or inability of T-regulatory cells to keep autoreactive T-Cells in check.  Genetic mutation, particularly in HLA genes, can promote autoimmune disease, as can environmental factors which degrade the body's tissues making them stimulate the immune system.

2.  Since the book has stopped introducing entirely new immune system components and mechanisms, the material has grown easier to understand.  Most challenging passages can be understood by referring back in the text.  I think the most challenging concepts for me to understand where the actual presentation of autoimmune disease in humans.  The symtpoms seem to be quite various and not always consistent from case to case for any particular disease (SLE, for instance), and though the underlying mechanisms are mostly clear, the presentation seems less so, I wonder if doctors have difficulty distinguishing between autoimmune disease and type II, III and IV hypersensitivity, as the mechanisms are identical.

3.  The book mentions how auto-reactive T cells are common even in healthy individuals, this leads me to question the efficacy of the negative selection system taking place in the thymus.  How are these auto-reactive cells making their way into the bodies circulation?  If the thymus could do it's job more effectively, there wouldn't be a need for T-reg cells, though as it is  I suppose I'm glad we've got them.  What are the exact mechanisms for negative selection in the thymus?  Is it possible for the body to prevent every potential T-cell with a cross section of every self-antigen it may encounter?  How does this presentation work?  Is the thymus the most diverse organ in the body, a meltin pot of self-peptides?  This idea intrigued me in chapter 5 as well.

Chapter 10

I am going to blog on Ch 10 this week

1. Chapter 10 is concerned with "over-reactions of the immune system", more commonly known as "allergic reactions". These reactions fall into 4 hypersensitivity groups: Type I which generally occurs through inhalation of antigen and its binding to IgE bound to its Fc receptor, particularly mast cells, which degranulate and release inflammatory mediators; Type 2 is caused by small molecules which bond covalently to components of the human cell surface and provoke B cell IgG antibody response; Type 3 occurs when soluble protein antigens bind to IgG specific to them causes inflammation; and Type 4 which involves antigen T-cell interaction and inflammatory response. The chapter spends the majority of its time going in depth into type 1 hypersensitivity reactions, so I will summarize this section: the first time a subject encounters an antigen, if the subject makes IgE antibodies for it, that antigen will become an allergic response. IgE antibodies have the highest affinity possible for an antibody and an Fc receptor, and the interaction is considered irreversible, thus the IgE antibodies act as "receptors" for mast cells, basophils and eosinophils which, once they encounter antigen again, will react very quickly and dramatically, releasing their granules and causing an allergic reaction, a reaction believed to have evolved to combat parasites.

2. Concerning the Type 1 allergic reaction, it is a bit unclear to me why it may arise in some people but not others. For this reaction to take place, a person must be exposed to an antigen, the antigen must be taken up by professional antigen presenters like dendritic cells, a Th2 Cell must then recognize the antigen and recruit a B cell to make IgE specific to that antigen. It seems this chain of events is unlikely to all occur for a small amount of harmless antigen but apparently it does and this then is an allergy. My question, though, is why this doesn't eventually happen to everyone. It seems like if we are repeatedly exposed to items such as peanuts, say, this chain of events would eventually happen to everyone--we would all become allergic to peanuts! Why doesn't this happen?

3. I am mainly baffled at the existence of these cell types (mast cells, basophils, eosinophils). I had always wondered what exactly these cells particular functions are, and I continue to wonder! It seems they exist as a sort of historical tool which may have once been helpful against parasitic infections and are now more trouble then they're worth (at least in many populations where exposure to parasites is quite low). Is there perhaps some way to inhibit IgE formation? It seems this antibody is of no use outside of provoking allergic reactions, and if we were to architect a method for stopping its production we could effectively strip these useless cell types of their receptors, rendering them harmless--perhaps an IL-4 inhibitor?

Post for October 6th

I've got a really busy weekend so I'm going try and post for Monday today. Because chapter 8 is so huge, I am just going to blog on the first segment, the innate immune response segment, in order to maintain some semblance of following the 3 sentence guidelines.

1. The first section begins by identifying the broad classes of possible infections (virus, bacteria, fungi, parasites) and then continues to identify the different parts of the immune system which combat them. First there is epithelial tissue, which provides a physical barrier of protection against invading agents and has chemical defenses as well (lysozyme in tears and saliva, acid and hydrolytic enzymes in the stomach, and antimicrobial peptides called defensins, which are found on all epithelial surfaces), finally, non-pathogenic flora inhabit many epithelial tissues and compete with possible pathogens for space and nutrients in a defensive way. The next line of defense are complement proteins which can work with antibodies to opsonize pathogens so they may be phagocytosed by macrophages, the next main line of defense. Macrophages are long lived, matured monocytes which inhabit connective tissues and phagocytose pathogens and release cytokines which recruit other cells to defend their tissue, causing a state of inflammation; they are guided by complement proteins and also by the adaptive immune cells. Another, primary, form of the innate immune response are the neutrophils, which are short lived and circulate in the blood, waiting for an inflammatory mediator signal from a tissue to bring them to the site of infection where they will phagocytose microorganisms and kill them with a collection of damaging chemical agents--primarily toxic oxygen radical species. The chapter continues to tell the functions of various excreted cytokines and of NK Cells which are a third form of immune lymphocyte which can be stimulated to very effectively kill invading cells and release cytokines.

2. The main challenge of this chapter for me was its sheer magnitude. I have above summarized only perhaps 1/4 of the main ideas in the chapter, and at only 1/8 the detail! Some mechanisms also came across a bit foggy to me; macrophages seem to recognize pathogens for phagocytosis with some fairly generalized receptors, if macrophage receptors dont have the same genetic variation as the adaptive immune cells how can they recognize pathogens without also being self reactive? If macrophages can use these more general and yet still not self-antigen receptors to kill invaders, why the need for the highly specialized adaptive immune system?

3. I found this chapter very enlightening with respect to the physical organization of all of these immune cells within the body, and this physical organization really helped me to learn each cell types particular functions. The distinction between the blood stream and outer tissues is a big one and I found these environments helped me to understand how and why different cells exist in different places (lower numbers of long lived, effector-cell-recruiting macrophages in the tissue vs. high numbers of short lived, quickly circulating neutrophils in the blood, for instance). The spatial organization of these cells within the body made a lot of sense to me and really helped me to grasp the particular names and functions of all these different immune cells.

Chapter 5

I wasn't in class last week but I was informed we are expected to focus our posts on chapter 5, as that's where we are in lecture.

1. The first half of chapter 5 discusses T cell receptor development. The gene rearrangement process which takes place here is quite similar to that found in B cells, but the way in which the rearrangements occur is more complex: first it is determined if a T cell will express an Alpha Beta or a Gamma Delta receptor, based on if a successful Beta-chain gene rearrangement occurs before a successful rearrangement of the the Gamma and Delta chains (this statistically leads to the majority of T cells differentiating to become Alpha Beta), once the successful Beta chain is expressed the T cell than proliferates before attempting to express a successful Alpha chain and also expresses the co-receptors CD4 and CD8, successful rearrangement leads to a "double positive"T cell which is then selected for to insure no self-antigen reactivity. In the initial "positive selection"portion of this stringent selection process, T Cells are tested for their capability to recognize the antigen-presenting MHC molecules of the host, and those with receptors that can interact with the MHC molecules are kept (at most 2%) while the rest are left to die by apoptosis. T cells then undergo negative selection, wherein they interact with dendritic cells and macrophages--profesional antigen-presenting cells--and are induced to undergo apoptosis if they interact with any self antigens.

2. I think my biggest challenge throughout both the B and T cell chapters has been conceptualizing the genetic machinery which facilitates rearrangement and all of the particulars of the V, D, and J segments, how they are arranged, how RAG actually facilitates this, and how, exactly, it is possible for T cells to rearrange up to four times. Also much of the medical terminology when describing locations within the body, particularly concerning the thymus (such as subcapsular epithelium, cortico-medullary junction, etc...) did little to further my understanding of the nature of these spaces.

3. I found it particularly interesting that the Thymus is a somewhat transitive organ, working primarily during development and childhood and becoming almost unnecessary be 30 years of age--is this perhaps a function of immune memory? Like the body decidind it has encountered as many new infections as it will and that the current memory immune cells can maintain the body's T-cell immunity without further novel T cell synthesis? It would be interesting to see how maintaining human Thymus function after the age of 30 might affect immunity, and other factors such as metabolism (as it seems perhaps the thymus is "discontinued"for energy reasons).

Reading #3

I was not able to get through chapter 5 before midnight tonight, mainly due to a monster chem problem set i have due tomorrow, so I will just be posting on Chapter 4 tonight.

1. Chapter 4 deals with B cell development in great depth, describing the genetic steps taken to create the immunoglobin receptor on each B cell which will determine the B cells fate (incorporationn into the lymphatic system and blood vessels, self-antigen recognition and light chain rearrangement, self-antigen recognition and apoptosis).

2. I was (as usual) challenged by the large lexicon of genetic terms which the book draws from to describe the process of heavy and light chain development. I was also a bit confused with the mechanism which distinguishes between giving a B cell a second strike at not being a self antigen and at what point an auto-immune reacting B cell is marked for apoptosis.

3. I found myself particularly interested in the selection process of immature B cells. This part of the chapter didn't go as far in depth as I had hoped with the actual mechanism of B cell selection, so much as it just described what actions took place, but it was still interesting to see how B cells are screened through interaction with potential "self-antigens", and that they might be modified through light chain rearrangement for a second try at not reacting in an auto-immune fashion before they are sent to their death.

For tomorrows Saturday Lecture

1. The first article I read was an overview article which looked like it might have been written for a popular weekly magazine-type audience; the article discussed the promising attributes of stem cell research and how they might be used to develop into cells a damaged body is deficient in--if only they weren't rejected by the host. The second article particularly discussed Hematopoietic Stem Cells (HSCs) which have been widely researched and observed to develop, when properly stimulated, into a number of various body cells. The final article I read was an in depth journal article which used flow cytometry and other staining methods to determine which of a multivariable collection of HSC types could survive in various regions of a host mouse and for how long.

2. These readings varied quite dramatically in terms of accessibility for me--ranging from overly simplified (and quite appreciated) background information, to the journal article on HSC that I found barely comprehensible. The biggest challenge in reading the article was all of the abbreviations which the authors assumed the readers to be well versed in. I am afraid that to really comprehend what was being said I would have needed to go out and read five more articles explaining the origin of such terms as the c-kit+ (K) lineage -/lo--what the heck does this mean?

3. I found the "Biological Perspectives" article particularly interesting, and enjoyed the level of detail it went into (too little, too much, juuuust right). I like the idea that "niches" along the surface of the cells which HSCs interact with could have a hand in determining those HSCs ultimate identity. I also found the work done in the FLK-2 journal article to determine which stem cells lasted for how long and tying these lifetimes down to particular markers very cool.

Reading #2

Note: I realized after publishing my first blog entry that we were meant to only share our thoughts on each question in three sentences or less--I will attempt to do this from now on and apologize for my obscenely long prior response.

1. Chapter 2 is all about B cells, how they develop, how they react to an antigen, and the various types and structures of immunoglobin proteins which they can produce to carry out this reaction. Particularly, chapter 2 focuses on the gene rearrangement mechanisms which introduce diversity into the antigen receptor portion of the Immunoglobin protein. Chapter 3 goes in to the same subjects as chapter 2 but with respect to T Cells, who share many similarities with B cells in regards to their antigen receptor's structure and the mode by which these receptors gain diversity to recognize many types of foreign molecules (gene rearrangement). Chapter 3 also discusses the MHC which presents antigens to T cells either intra or extracellularly (by either MHC I or MHC II respectively), and is a fundamental difference between B cells (which don't need antigens to be 'presented' to them and which may eject antibodies) and T cells (which depend on MHC to present antigens, and which do not secrete antibodies).


2. I found the highly specific and in depth method of classifying and discussing the various structural aspects of immunoglobin a bit overwhelming, and was often having trouble following the abbreviations used in the text. I found myself a bit confused when trying to differentiate between gene rearrangement, as used to produce Ig and T cell receptors, and the production of MHC which, though the book stresses is not formed by gene rearrangement, nonetheless seems to be drawing genetic information from a large collection of gene families--what is the difference between this and gene rearrangement?


3. I found the diversity of the immunoglobin classes logical and the many methods by which this diversity is achieved quite interesting. I also found the figures at the end of Chapter 2 very helpful in summarizing the structure and genetic origin of immunoglobin, as well as the genetic changes it undergoes throughout a B cell's development. I found chapter 3 more accesible than chapter 2 as it was touching on many ideas which were already described in chapter 2--I think that upon re-reading these chapters many of the genetic subtleties which eluded me on the first run through will make more sense.

Chapter 1 Reading

Q1: The first chapter of our immunology text outlines the basic pieces of the immune system and how different elements react to different invading pathogens to defend the body. We learn that the most fundamental immune system defense is the physical barrier of our skin and the mucosal surfaces which protect other physical cavities. If a breach of the skins barrier does occur, via a scratch or cut for instance, the innate immune response is triggered. In such a case, the point of infection is detected by effector cells who release cytokines which cause inflammation at the site allowing other immune system cells and molecules to pass in to the tissue.
Chapter 1 goes on to outline all of the major types of immune cells which sprout from the bone marrow. I won't go into each type here, but will mention the three main lineages: lymphoid, myleoid, and erythroid all of which divide and differentiate into various other forms which specialize to combat specific kinds of pathogens. In particular, the book discusses the various forms of lymphoid cells and the lymphatic system where they are found. It goes in depth into how an infection may be transported to a lymph node by dendritic cells and how helper T Cells may stimulate the division of pathogen specific B cells to be sent to the site of infection. This response by T cells and B Cells is what is referred to as addaptive immunity.
The specifics of adaptive immunity are further outlined in chapter 1, and we see that T-Cells and Immunoglobins (B-Cells) can adapt to specific pathogens by varying amino acid sequences in their structures. These variable sequences bind to particular antigens which are designed to combat a specific pathogen. Such specificity is achieved in B and T cells by gene rearrangement, which occurs throughout the lietime of the organism and is referred to as somatic recombination. The antigen recognition function is what distinguishes B cells from T cells. B cells bind to a "native protein antigen" extracellularly, while T Cells bind to a "processed" peptide antigen which is derived from the denatured native protein. This occurs within the cell.
The function of different types of T cells is discussed in detail, and we learn how T Cells actually comabt pathogens by coordination with the major histocompatibility complex (MHC) of which there are two types: MHC I, which works within the ER of the cell, and MHC II which works within Macrophages and B Cells, and bind to helper T Cells. The production and stringent screening of T cells to produce self tolerant lymphocytes which won't attack the body is also mentioned. Immunoglobins are also mentioned, which facilitate the engulfment and phagogcytosis of pathogens by neutrophils and macrophages.
The chapter goes on to discuss how immunity can occur when the secondary immune response defeats an infection before any visible signs of disease present themselves. Data is presented to show how effective vaccination programs have been in producing an immunity in the majority of the world population for many once common diseases. It also describes how genetic deficiencies may affect immune responses and make certain individuals susceptible to diseases which are generally easily combatted by the immune system. Such diseases are known as immunodeficiency diseases. The chapter also goes in to how the immune system may fail to recognize proper invasions and overreact towards harmless antigens--such a reaction is called allergic, or hypersensitivity. At its worst, improperly responding immune cells may degrade some target tissue to cause autoimmune diseases. In such a case a regularly healthy human cell is attacked, and the function lost. Insulin dependent diabetes is an example of such an autoimmune response towards Beta cells in the pancreas.

I also read the biography on Metchnikoff and his discoveries of phagocytes and a syphillis treatment. It was very lyrical and more theatrical than scientific, but nonetheless quite interesting. Metchnikoff performed some incredible experiments with a wide range of organisms to argue his theory of phagocytes as the immune system's sole combatant.

Finally I read the history of Elrich and his overly complex and partially flawed side chain theory. Though incorrect in its whole, the theory built the foundation for the modern understanding of the immune system. The idea that disease causing toxins interact with specific side chains on cells to produce a response which then remains in circulation within the body is essentiall correct, and was an important contribution to modern immunology.

Q2: I found the material in chapter 1 to be rather challenging in its breadth. I have only been slightly introduced to immunology before this class, and I felt a little bit like a child jumping in to the deep end. But it was also very enlightening, there were several "oh yeah" moments during my reading which were rewarding and I found the material to be very interesting. In particular, the scope of different immune cells all of which derive from the bone marrow I found overwhelming, along with the depth in which the book discusses the lymphatic system, B, and T Cells. I also was having some vocabulary problems, I found myself looking up antigen, and wondering if an antigen is necessarily the invading bacteria or could it be some other signal? I also found the various MHC-T cell interactions to be a bit complicated.

Q3: I was especially engaged by the chapter 1 reading. I found some of the material difficult, and perhaps too broad, but look forward to going in depth into the various mechanisms of the immune system. It is particularly exciting to see how something like an autoimmune response attacking Beta cells in the pancreas develops into Type I Diabetes. I have always wondered why this disease took many years to onset, and the gradual erosion which occurs in this particular autoimmune response explains this.

Post #1

1. My name is David Lawrence.

2. I am a senior and will be graduating a semester early at the end of the Fall.

3. I aspire to go to medical school and become a doctor. I can't say for sure yet what field of medicine, but cardiology interests me as well as all forms of surgery. I also enjoy working in the lab and have entertained the idea of becoming a research scientist towards some form of medical advancement.

4. I hope to learn something which will apply to my work one day as a doctor or medical researcher. As someone who intends to continue on to medical school, I am embarrassed at how little I know about the human body and hope that this class will teach me something in this area. I am excited in particular to learn about cancer and HIV/AIDS in depth.

5. Scientifically, both organic chemistry I and II really stimulated me and inspired me to continue on with a scientific degree. I enjoyed learning from a simple set of foundational rules and guidelines to predict complex reactions and outcomes. I also recently took creative writing and finally understood what it was like to take a "Macalester" class here--it was the most fun I have ever had in a course and I genuinely enjoyed doing every bit of work I put in to it.

6. You know, this is the second or third time this question has come up in the last few days--weird. Having many opportunities to consider this, I have settled upon mint chocolate chip.