Overview of the Immune System

Overview of the Immune System The Humoral Response B Cells and T Cells Working Together 

Antibody Diversity Is Augmented by Unique Genetic Mechanisms 

The Complement System Facilitates Removal of Microorganisms and Antigen-Antibody Complexes The Cell-Mediated Response A Separate Response by T Cells 

Tolerance Prevents the Immune System from Attacking Self-Antigens 

A thorough review of the immune system is not the intent of this chapter, but a brief descriphon of the important components of the system and their interactions is necessary for an understanding of how xenobiotics can affect immune funchon. A breakdown at any point in this intricate and d5mamic system can lead to immunopathology. 

Annotations in right margin indicate location of text describing specific advice. 

Examples include myelosuppression, histopathology in immune associated tissues, increased infection, tumors, decreased serum Ig, phenotypic changes in immune cells. 

Other acceptable assays include drug effect on NK cell function in vitro bastogenesis, cytotoxic T-cell function, cytokine production, delayed-type hypersensitivity, host resistance to infections or implanted tumors. 

Examples include anemia, leukopenia, thrombocytopenia, pneumonitis, vasculitis, lupus-like reactions, glomerulonephritis. 

This overview provides a superficial description of the immune system, focusing primarily on those aspects which may be impacted by pharmaceuticals unintentionally. For a more thorough review of the immune system, there are some excellent books on the subject (Murphy, 2014 Abbas et al., 2015). The immune system is traditionally categorized into two compartments based on how antigens are recognized innate immunity, which is nonspecific and does not require prior exposure, and acquired immunity, in which exposure 

As the immune system evolved as a means to protect the body from infection and eliminate cells (e.g., virus containing, senescent, or tumor cells), various mechanisms (e.g., anti-inflanunatory cytokines, regulatory T cells) also evolved to limit or mitigate the damage to normal tissues caused by an immune response or prevent attack on normal cells. Uncontrolled immunostimulation may result in circulatory collapse or damage to tissues, which may be life threatening. 

Some examples of in vitro assays for immunotoxicity assessment follow (Table 13.1), but this list is not intended to be comprehensive. It should be borne in mind that this is a rapidly growing area of research, and many of the assays employed in immunotoxicity or immunosafety evaluation of pharmaceuticals are fit-for-purpose assays based on mechanism or target and are beyond the scope of this chapter. Evaluation of effects on individual cell types and mechanisms (e.g., neutrophil, macrophage, cytotoxic T lymphocyte, and NK function) will not be discussed, as these are rarely employed unless driven by STS findings or intended mechanism of action. 

TABLE 13.1 Examples of In Vitro Testing Assay for Immunotoxicity Assessment 

Human lymphocyte activation assay (HuLA) Proliferation, flu antigen-specific IgG Immunosuppression CoUinge et al. (2010) 

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OVERVIEW OF THE IMMUNE SYSTEM AS A SOURCE OF DRUG TARGETS... 

Hofmeyr SA. 1997. An overview of the immune system, http //www.cs.unm.edu/ immsec/html-imm/introduction.html. Retrieved 8/7/07. 

Immunotoxicology is the study of undesired effects resulting from the interactions of xenobiotics with the immune system (Figure 19.1). There is evidence that some xeno-biotics can cause immune suppression. Xenobiotics can also interact with the immune system to either cause or exacerbate allergic disease. Finally there is growing concern that xenobiotics could have some involvement in autoimmune disease. This chapter provides a brief overview of the immune system, chemicals associated with immune suppression and immune pathologies, and approaches to testing for these effects. 

The immune system is a complex body system whose various functions display a high level of inter-regulation. As such, any attempt to describe the functioning of the immune system within a single chapter will inevitably represent an oversimplification. However, the authors consider this chapter to be a comprehensive, but nevertheless basic, overview of the immune system that will serve as a sound foundation for further reading on the clinical immunological basis of disease or for the consultation of more specialized texts on immunological function. 

To provide a better understanding of the stndies discnssed in this section and to provide perspective on the relevance of snch effects on human health, an overview of the immune system is provided below. 

The following list provides an overview of the variety of possible defense mechanisms of the immune system after an antigen-antibody reaction has taken place ... 

Chemokines are a family of small, structurally related molecules that play a fundamental role in the development, homeostasis, and function of the immune system (overview provided in Chap. 1). Four closely related subfamilies of chemokines have now been characterized (13,14). Of these, members of two subfamilies in particular have definitively been shown to participate in pulmonary antimicrobial host responses. The ELR+ CXC chemokine family members, which includes CXCLl-8 and CXCL15, have predominant neutrophil stimulatory and chemotactic activities, whereas the ELR CXC chemokines and CC chemokine family exerts predominant chemotactic and/or activating effects on macrophages, specific T cell populations, and/or eosinophils (14). Several lines of evidence would suggest that CXC and CC chemokines represent integral components of antimicrobial host defense. First, the well characterized in vitro and in vivo leuko-... 

The overview of innate immune system activation on material surfaces (see Section 4.6) assumes that the inherent properties of the material remain constant over time and that the response is mainly due to the protein adsorption onto the material surface. However, the situation is more challenging when it comes to biodegradable materials, because they (obviously) will change in surface topography and size over time. In addition, because the degradation of most commonly used materials leads to the production of hydroxyl acids and eventually carbon dioxide, a lowering of the pH in the adjacent tissue is found. This change in pH leads to a dramatic increase in complement activation and opsonization [4], and to increased inflammation. 

Brandtzaeg, P. Overview of the mucosal immune system. Curr Top Microbiol Immunol 146 (1989) 13-25. 

In this context, the main objective of this chapter will be to provide an overview to the shucture and organization of the nervous system that is relevant to the understanding of the unique interactions between the nervous and the immune system and to elucidate the pathogenesis of Alzheimer s disease (AD), Parkinson s disease (PD), HTV encephalitis (HIVE), and other neurodegenerative and neuroinflammatory disorders (Ringheim and Conant, 2004 Gendelman, 2002 Ho etal., 2005). 

As indicated by this brief overview there is considerable evidence for a close relationship between changes in the immune system and depression, particularly MDD. Whether there is a clear cause and effect relationship between these is not known in most cases, although there are sdrong data in the case of IL-6 and IFN-a, as noted. It will be important to determine more clearly the exact relationship between depression and immune system alterations. There is also a need to determine which of the immune alterations that are found are clinically important (Irwin, 2001). 

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