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This chapter explains how mold spores can cause allergies. Spores carry proteins on their surface, and those that act as antigens can cause a cascade of immune responses resulting in the miseries of allergic rhinitis or hay fever, allergic conjunctivitis, skin allergies, asthma, eczema or atopic dermatitis, and hypersensitivity pneumonitis. This chapter describes interactions between immune cells in allergies mediated by IgE and IgG, providing a primer on this complex field of medicine. The idea that allergy is a perversion of a response that evolved to combat parasitic infestations is discussed, along with the hygiene hypothesis that has been advanced as an explanation for the increasing prevalence of asthma.

The Major Histocompatibility Complex on chromosome 6 encodes a diverse array of genes involved in the immune and inflammatory response. The region is remarkably polymorphic and has been associated with susceptibility to autoimmune and infectious disease. The approaches to defining and understanding the nature and consequences of genetic diversity in the MHC are reviewed in terms of the biology of encoded molecules, evolutionary selective pressures and relationship to disease. Progress in haplotypic analysis of the MHC, resequencing and fine mapping are discussed together with insights from structural biology and detailed functional characterisation of the consequences of genetic diversity. The role of genetic variation in the MHC for a number of specific diseases are reviewed including rheumatoid arthritis, haemochromatosis, type 1 diabetes, coeliac disease, narcolepsy and sarcoidosis with emphasis on progress in defining the functional basis of disease associations, for example modulation of alternative splicing by genetic variation associated with sarcoidosis.

This chapter begins with a brief overview of the different brain phagocyte populations in regard to the kinetics of their permanent supplementation by blood-derived precursors. It then provides a timely view of how (astro)glial cells regulate the local adoption of invading antigen-presenting cells (APCs).

This chapter discusses antigen processing, presentation, and T cell interaction. The central nervous system (CNS) is protected by a blood-brain barrier (BBB) designed to minimize the passage of immune cells and macromolecules into the brain parenchyma. In the normal CNS parenchyma antigen-presenting cells (APCs) are functionally inactivated and lack expression of major histocompatibility complex (MHC) molecules. Nevertheless, the CNS is routinely surveyed by activated T lymphocytes. Perivascular macrophages situated adjacent to the endothelium cells of the blood vessels take up and present antigens to T lymphocytes. Most cells of the brain parenchyma are immunologically quiescent in the healthy CNS, but can be stimulated to become facultative APCs that process and present antigens via their MHC molecules to T lymphocytes in neuroinflammatory diseases.

This chapter investigates the different definitions of immunology, in particular the dominant definition stating that immunology is the discipline that studies the defense of organisms against pathogens. The different steps towards the autonomy of immunology as a discipline are examined, from immunization to the elaboration of a theory of immunity, and eventually the institutionalization of the domain. I propose my own definition of immunology as the discipline that studies specific interactions between immune receptors and antigenic patterns, triggering mechanisms that destroy or prevent the destruction of target antigens. I show that, contrary to what has long been believed, every organism has an immune system. I describe several examples of immune systems (in mammals, insects, plants, and even unicellulars). I close this chapter by an analysis of the concepts generally considered as central in immunology, those of “self” and “nonself.”

This chapter offers a new theory in order to explain the triggering of an immune response, called the “continuity theory.” According to this theory, the triggering of an immune response is due to a strong modification of the antigenic patterns with which the organism’s immune receptors continuously interact. The continuity theory is built upon the two observations made in the previous chapter in order to reject the self-nonself theory, that is, normal autoreactivity and immune tolerance. One of the main advantages of the continuity theory is that it gathers under a unique explanation phenomena that have until now received different explanations, and even sometimes ad hoc explanations: immune responses to tumor cells, the phagocytosis of dying cells, or the triggering of immune regulatory mechanisms, among others. I show how the continuity theory explains a wide range of phenomena, and how it can be applied to every organism, including unicellulars.

This chapter compares the continuity theory that I propose with the other theories available in today’s immunology, including the self-nonself theory, the systemic theory of the immune “network” (Jerne), the autopoiesis framework (Maturana, Varela, Coutinho), the self-organization theory (Cohen and Atlan), and the danger theory (Matzinger). I emphasize the aspects that the continuity theory borrowed or inherited from these theories, as well as the many aspects on which it differs from them. I show that some frameworks elaborated to understand the immune system are not genuine scientific theories, but rather mere “viewpoints” on immunity. I insist that no framework has, up to now, succeeded in taking into account the importance of both innate immunity and immune tolerance – two aspects that are at the center of the continuity theory.

This chapter describes the use of computer modeling to quantify the link between prostate-specific antigen (PSA) screening and prostate cancer incidence and mortality. Data resources for both cancer surveillance and PSA screening are outlined and an approach to modeling both prostate cancer mortality and incidence is presented. The models can be formalized as a statistical framework for inference by developing a likelihood function for the key variables that link PSA screening and prostate cancer incidence. The chapter also reviews alternative modeling approaches and other methods that have been used to address the link between PSA screening and population trends in prostate cancer mortality.

This chapter discusses how the human immune system combats viruses, either by spontaneously eliminating infections or by becoming stimulated via vaccination to prevent viral diseases. The proteins in viruses and bacteria that trigger an immune response are called antigens or immunogens, and the result of a satisfactory immune response to these antigens is immunity—long-term protection from repeated disease caused by a specific type of virus or bacteria. Similarly, a vaccine primes the immune response by programming it to anticipate and resist future pathogens like those in that particular vaccine. The immune system has evolved to deal with enormous numbers and varieties of every conceivable foreign antigen. However, the immune system must discriminate between foreign antigens, such as viral proteins, that are non-self and those antigens that are self, one’s own proteins (i.e., hormones such as insulin and cell proteins that make up muscle or nerve cells). Ultimately, the success of this system defines an organism’s capacity for survival.

For many years, the dream of bioethics has been to confide medical decisions to patients and not to doctors. The favoured key to doing so has been the doctrine of informed consent. The success of informed consent depends on two things. First, patients must be able to understand and remember the information doctors give them. Secondly, patients must be able to analyse that information and use it to make a decision. The first of these requirements has been studied extensively. The second requirement for the success of informed consent has, in contrast, been virtually unstudied. This chapter examines a case study involving prostate-specific antigen (PSA) screening to gain further insight into the way patients think about their medical choices.

This chapter focuses on the nature of Toxoplasma gondii—an obligate, intracellular, parasitic protozoan that causes the disease toxoplasmosis. This parasite is mostly acquired by eating fecally contaminated water and food that contains their eggs or larvae. Once inside the body, it quickly inhabits a cell by secreting apical membrane antigen 1 (AMA1) that facilitates the interaction of the parasite's outer membrane with the host cell membrane, resulting in the formation of a tight junction between the two. The immune system responds to the infection by ramping up the production of interleukin, a messenger peptide that would signal other components of immune system to fight the foreign body. However, the parasite would modify the infected cell membrane to form an outer wall of the tissue cyst to serve as a barrier.

This chapter discusses how monoclonal antibodies (Mabs) opened new frontiers in research well beyond immunology and transformed the way scientists analyzed biological phenomena in the early 1980s. Some of the earliest discoveries made possible by Mabs were related to the brain and the central nervous system. Yet these advances were just the tip of the iceberg as scientists began to realize the power of Mabs for exploring the vast number of human differentiation antigens, proteins located on the cell surface of immune cells. Before the arrival of Mabs, scientists had little knowledge of the surface of immune cells. Their subsequent investigations into human differentiation antigens would not only advance understandings about the network of interactions that govern the immune response, but also help identify new targets for diagnostic and therapeutic interventions that would have profound implications for human health.

This chapter considers the development of monoclonal antibodies (Mabs) for cancer treatment. In the early 1980s, many scientists were optimistic that Mabs would defeat cancer. In 1982, John Minna of the U.S. National Cancer Institute (NCI) predicted that Mabs would revolutionize cancer diagnosis within five years. The adoption of Mabs as probes for targeting and identifying the multitude of antigens on different cell types seemed to herald their use in detecting and classifying tumors on a hitherto unthinkable scale. Mabs also promised to deliver more precisely powerful tumor-cell-killing agents, such as chemotherapeutic drugs, radioactive isotopes, or toxins, and to provide a way of harnessing a patient's immune system to attack tumors. However, work in the cancer field proved less straightforward than anticipated, partly because much of the initial endeavor was undertaken by researchers in academic laboratories and clinics with limited resources. Funded by government and charitable sources, their work had only minimal support from industry. In addition, new cancer drugs faced stiff regulatory and ethical tests.

There are five species of Plasmodium that can cause malaria in humans but 95% of cases are due to Plasmodium falciparum (Africa) and Plasmodium vivax (south-east Asia and South America). Malaria is transmitted by female mosquitos, usually Anopheles species, when they take a blood meal. The malarial parasite has a complex life cycle but when in humans it spends most of its time in liver and blood cells where it is protected from host defences. This makes the development of an effective vaccine difficult but a potential vaccine that targets the immediate post-infection phase is being trialled. Genomic analysis has shown that Plasmodium falciparum and Plasmodium vivax are only distantly related. Plasmodium falciparum arose following a species jump from gorillas to humans about 10,000 years ago when localized populations were developing following transition from hunter/ gatherer to farmer. It was thought that Plasmodium vivax arose in Asia but the presence of close relatives in African apes plus the natural resistance of Africans to it suggest that it arose in Africa and ‘escaped’ to Asia. The most effective treatment for malaria is artemisinin-based combination therapy but resistance to artemisinin is developing.

There are two species of Salmonella. Only Salmonella enterica infects warm-blooded animals. The sub-species Salmonella enterica subsp. enterica is the only one to infect humans and other mammals. Infections of humans are the result of the ingestion of certain serotypes of Salmonella enterica subsp. enterica. Typhoidal serotypes cause typhoid fever and non-typhoidal serotypes cause food poisoning. Both typhoidal and non-typhoidal serotypes need to cross the wall of the intestine but do so in different ways and using different effectors. Typhoidal serotypes produce typhoid toxin and pathogenicity is enhanced by the presence of the Vi antigen. They have undergone genomic degradation by losing the function of certain biosynthetic genes present in non-typhoidal serotypes. There is little genomic variation in typhoidal serotypes isolated from different parts of the world whereas non-typhoidal serotypes show a great deal of variation. In sub-Saharan Africa there is evidence that non-typhoidal serotypes are undergoing genomic degradation and becoming invasive.

Prostate cancer is the most common solid tumor and the second leading cause of cancer-related mortality in American men. Worldwide, prostate cancer ranks second and fifth as a cause of cancer and cancer deaths, respectively. Despite the international burden of disease due to prostate cancer, its etiology is unclear in most cases. Established risk factors include age, race/ancestry, and family history of the disease. Prostate cancer has a strong heritable component, and genome-wide association studies have identified over 110 common risk-associated genetic variants. Family-based sequencing studies have also found rare mutations (e.g., HOXB13) that contribute to prostate cancer susceptibility. Numerous environmental and lifestyle factors (e.g., obesity, diet) have been examined in relation to prostate cancer incidence, but few modifiable exposures have been consistently associated with risk. Some of the variability in results may be related to etiological heterogeneity, with different causes underlying the development of distinct disease subgroups.

Because of the great importance of the surface properties of the polysiloxanes, this topic is treated separately in this chapter. Hydrophobic polysiloxanes having simple aliphatic or aromatic side groups have surfaces that show essentially no attraction to water. In fact, polysiloxanes can serve as water repellants. This property is very useful for applications such as protective coatings on historical monuments and for controlling the surfaces of other polymers, sensors, and quantum dots. Hydrophobic surfaces can be readily regenerated if the surface becomes damaged. Regeneration occurs by rearrangements of the polysiloxane chains so that the hydrophobic methyl groups are once again covering the surface. The flexibility of the siloxane chain backbone facilitates this process. It is also possible to prepare hydrophobic films using methyl-modified siloxane melting gels. Glass surfaces or wool fibers can be coated with polydimethylsiloxane (PDMS) to make them more hydrophobic. In some cases, it is necessary to modify a polysiloxane surface to make it hydrophilic or hydrophobic. Hydrophobization is one aspect of the general topic of modifying and managing the properties of polymer surfaces. An important example involves soft contact lenses that contain PDMS, which is often used because of its very high permeability to oxygen, which is required for metabolic processes within the eye. Such lenses do not feel comfortable however because they do not float properly on the aqueous tears that coat the eye. There are a number of ways to modify the surfaces. There is even a way to make “unreactive” silicones react with inorganic surfaces. In some applications it is useful to have hydrophilicity in the bulk of the polymer instead of just at the surface. One way of doing this is by simultaneously end linking hydrophilic poly(ethylene glycol) (PEG) chains and hydrophobic PDMS chains. Another way is to make a PDMS network with a trifunctional organosilane R’Si(OR) end linker that contains a hydrophilic R’ side chain, such as a polyoxide. Treating only the surfaces is another possibility, for example, by adding hydrophilic brushes by vapor deposition/hydrolysis cycles. Such hydrophilic polysiloxanes can also serve as surfactants.

The first 1H NMR spectrum of a protein, bovine pancreatic ribonuclease, reported in 1957 by Saunders et al. was accounted for by Jardetzky and Jardetzky (1957) in terms of the spectra of the constituent ammo acids. Jardetzky and coworkers continued to report a series of important papers describing the potential usefulness of high-resolution NMR (Roberts and Jardetzky, 1970). Modern NMR of proteins began with the classic paper published in 1968 by Markley, Putter, and Jardetzky, who beautifully demonstrated the possibility of using stable-isotope labeling for the structural analyses of proteins in solution (Markley et al., 1968). Five years before the publication of this paper, Jardetzky gave an important lecture in Tokyo, stressing the importance of NMR particularly in combination with deuterium labeling as a potential solution version of X-ray crystallography for the determination of the three-dimensional structure of proteins (Jardetzky, 1965). The impact of Jardetzky’s contribution was great, eventually leading to the now well-established combination of multidimensional NMR and stable-isotope labeling for the determination of the three-dimensional structure of proteins in solution. High-resolution NMR of biological macromolecules takes advantage of the fact that 1H, 13C, and 15N, all of which are spin 1/2 nuclei, possess long relaxation times, which primarily are due to weak dipole-dipole interactions. Thus, phase memory can be retained long enough to extract relevant information on the spin system by fully making use of multidimensional techniques. This makes high-resolution NMR special as a tool for structural analyses at atomic resolution. By contrast, relaxation times are far shorter in the case of visible, ultraviolet, infrared, and Raman spectroscopy, where much stronger interactions are involved. For this reason no structural analyses at atomic resolution are possible using these types of spectroscopy. However, an increase in the molecular weight eventually creates difficulties in achieving sufficient spectral resolution to be able to separate and assign each of the resonances of a protein. This is due to 1) a limitation of the strength of static magnetic field available and more importantly 2) an unavoidable shortening of relaxation times originating from the slow tumbling motion of the protein molecules in solution.

The initiation and maintenance of an immune response to pathogens requires the interactions of cells and proteins that together are able to distinguish appropriate non-self targets from the myriadof self-proteins (Janeway and Bottomly, 1994). This discrimination between self and non-self is in part accomplished by three groups of proteins of the immune system that have direct and specific interactions with antigens: antibodies, T cell receptors (TcR) and major histocompatibility complex (MHC) proteins. Antibodies and TcR molecules are clonally expressed by the B and T cells of the immune system, respectively, defining each progenitor cell with a unique specificity for antigen. In these cell types both antibodies and TcR proteins undergo similar recombination events to generate a variable antigen combining site and thus produce a nearly unlimited number of proteins of different specificities. TcR molecules are further selected to recognize antigenic peptides bound to MHC proteins, during a process known as thymic selection, restricting the repertoire of T cells to the recognition of antigens presented by cells that express MHC proteins at their surface. Thymic selection of TcR and the subsequent restricted recognition of peptide-MHC complexes by peripheral T cells provides a fundamental molecular basis for the discrimination of self from non-sell and the regulation of the immune response (Allen, 1994; Nossal, 1994; von Boehmer, 1994). For example, different classes of T cells are used to recognize and kill infected cells (cytotoxic T cells) arid to provide lymphokiries that induce the niajority of soluble antibody responses of B cells (helper T cells). In contrast to the vast combinatorial and clonal diversity of antibodies and TcRs, a small set of MHC molecules is used to recognize a potentially unlimited universe of foreign peptide antigens for antigen presentation to T cells (Germain, 1994). This poses the problem of how each MHC molecule is capable of recognizing enough peptides to insure an immune response to pathogens. In addition, the specificity of the TcR interaction with MHC-peptide complexes is clearly crucial to the problem of self :non-self discrimination, with implications for both protective immunity and auto-immune disease.