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.